PDZ domain 2 of the full-length isoform of whirlin and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of the full-length isoform of whirlin and related domains. Whirlin is an essential protein for developmental pathways in photoreceptor cells of the retina and hair cells of the inner ear. The full-length whirlin isoform has two harmonin N-like domains, three PDZ domains, a proline-rich region, and a PDZ-binding motif. Whirlin isoforms may form different complexes at the periciliary membrane complex (PMC) in photoreceptors, and the stereociliary tip and base in inner ear hair cells. It interacts with ADGRV1 and usherin at the PMC; with SANS and RpgrORF15 at the connecting cilium in photoreceptors; with EPS8, MYO15A, p55, and CASK proteins at the stereociliary tip of inner ear hair cells; and with ADGRV1, usherin, and PDZD7 at the stereociliary base in inner ear hair cells. Mutations in the gene encoding whirlin (WHRN; also known as USH2D and DFNB31), have been found to cause either USH2 subtype (USH2D) or autosomal recessive non-syndromic deafness type 31 (DFNB31). Whirlin is the key protein in the USH2 complex (whirlin, usherin and GPR98) which recruits other USH2 causative proteins at the periciliary membrane in photoreceptors and the ankle link of the stereocilia in hair cells. Whirlin's interaction with espin, another stereociliary protein, may be important for the architecture of the USH2 complex. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This whirlin family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 278 EKKVNLVLGDGRSLGLTIRGGAEYGLGIYITGVDPGSEAESSGLKVGDQILEVNGRSFLNILHDEAVKLLKSSRHLILTV 357
Cdd:cd06741   1 ERKVNLVVEDGQSLGLMIRGGAEYGLGIYVTGVDPGSVAENAGLKVGDQILEVNGRSFLDITHDEAVKILKSSKHLIMTV 80

                ....
gi 57012340 358 KDVG 361
Cdd:cd06741  81 KDVG 84

first harmonin_N_like domain (repeat 1) of the long isoform of whirlin, and related domains; This subgroup contains the first of two harmonin_N_like domains of the long isoform of whirlin, and related domains. Whirlin is a postsynaptic density-95/discs-large/ZO-1 (PDZ) domain-containing scaffold protein which binds various components of the Usher protein network of the inner ear and the retina: erythrocyte protein p55, usherin, VlGR1, and myosin XVa. The long isoform of whirlin contains two harmonin_N_like domains, and three PDZ protein-binding domains, PDZ1-3. This first harmonin_N_like domain precedes PDZ1, and is a putative protein-binding module based on its sequence similarity to the N-terminal domain of harmonin. This first harmonin_N_like domain has been assayed for interaction with the cytoplasmic domain of cadherin 23 (a component of the Usher network and an interacting partner of the harmonin N-domain), however no interaction could be detected. The short whirlin isoform, derived from an alternative start ATG, lacks this first harmonin_N_like domain. The short isoform has in common with the long isoform, the second harmonin_N_like domain (designated repeat 2, not present in this subgroup), and PDZ3.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 57012340  38 ANVRQLHQALTALLSEPEREQFTHCLNAYHARRNVFDLVRTLRVLLDSPVKRRLLPMLRLVIPRSDQLLFDQYTAE 113
Cdd:cd07356   3 ANVRNLHVALTKLLSDAEREEFTHCLNCYHKNRNVYDLVQSLKVVLDSPEKRQLFPLLRLVIPRSDQALFDQYTSE 78

PDZ domain 2 of the full-length isoform of whirlin and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of the full-length isoform of whirlin and related domains. Whirlin is an essential protein for developmental pathways in photoreceptor cells of the retina and hair cells of the inner ear. The full-length whirlin isoform has two harmonin N-like domains, three PDZ domains, a proline-rich region, and a PDZ-binding motif. Whirlin isoforms may form different complexes at the periciliary membrane complex (PMC) in photoreceptors, and the stereociliary tip and base in inner ear hair cells. It interacts with ADGRV1 and usherin at the PMC; with SANS and RpgrORF15 at the connecting cilium in photoreceptors; with EPS8, MYO15A, p55, and CASK proteins at the stereociliary tip of inner ear hair cells; and with ADGRV1, usherin, and PDZD7 at the stereociliary base in inner ear hair cells. Mutations in the gene encoding whirlin (WHRN; also known as USH2D and DFNB31), have been found to cause either USH2 subtype (USH2D) or autosomal recessive non-syndromic deafness type 31 (DFNB31). Whirlin is the key protein in the USH2 complex (whirlin, usherin and GPR98) which recruits other USH2 causative proteins at the periciliary membrane in photoreceptors and the ankle link of the stereocilia in hair cells. Whirlin's interaction with espin, another stereociliary protein, may be important for the architecture of the USH2 complex. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This whirlin family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 278 EKKVNLVLGDGRSLGLTIRGGAEYGLGIYITGVDPGSEAESSGLKVGDQILEVNGRSFLNILHDEAVKLLKSSRHLILTV 357
Cdd:cd06741   1 ERKVNLVVEDGQSLGLMIRGGAEYGLGIYVTGVDPGSVAENAGLKVGDQILEVNGRSFLDITHDEAVKILKSSKHLIMTV 80

                ....
gi 57012340 358 KDVG 361
Cdd:cd06741  81 KDVG 84

first harmonin_N_like domain (repeat 1) of the long isoform of whirlin, and related domains; This subgroup contains the first of two harmonin_N_like domains of the long isoform of whirlin, and related domains. Whirlin is a postsynaptic density-95/discs-large/ZO-1 (PDZ) domain-containing scaffold protein which binds various components of the Usher protein network of the inner ear and the retina: erythrocyte protein p55, usherin, VlGR1, and myosin XVa. The long isoform of whirlin contains two harmonin_N_like domains, and three PDZ protein-binding domains, PDZ1-3. This first harmonin_N_like domain precedes PDZ1, and is a putative protein-binding module based on its sequence similarity to the N-terminal domain of harmonin. This first harmonin_N_like domain has been assayed for interaction with the cytoplasmic domain of cadherin 23 (a component of the Usher network and an interacting partner of the harmonin N-domain), however no interaction could be detected. The short whirlin isoform, derived from an alternative start ATG, lacks this first harmonin_N_like domain. The short isoform has in common with the long isoform, the second harmonin_N_like domain (designated repeat 2, not present in this subgroup), and PDZ3.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 57012340  38 ANVRQLHQALTALLSEPEREQFTHCLNAYHARRNVFDLVRTLRVLLDSPVKRRLLPMLRLVIPRSDQLLFDQYTAE 113
Cdd:cd07356   3 ANVRNLHVALTKLLSDAEREEFTHCLNCYHKNRNVYDLVQSLKVVLDSPEKRQLFPLLRLVIPRSDQALFDQYTSE 78

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340    138 EVRLVSLRraKAHEGLGFSIRGGSEHGVGIYVSLVEPGSLAEKEGLRVGDQILRVNDKSLARVTHAEAVKALKGSK-KLV 216
Cdd:smart00228   1 EPRLVELE--KGGGGLGFSLVGGKDEGGGVVVSSVVPGSPAAKAGLRVGDVILEVNGTSVEGLTHLEAVDLLKKAGgKVT 78

                   ....*..
gi 57012340    217 LSVYSAG 223
Cdd:smart00228  79 LTVLRGG 85

PDZ domain; PDZ domains are found in diverse signaling proteins.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 57012340   141 LVSLRRAKaHEGLGFSIRGGSEHGV-GIYVSLVEPGSLAEKEGLRVGDQILRVNDKSLARVTHAEAVKALKGSKKLV 216
Cdd:pfam00595   1 QVTLEKDG-RGGLGFSLKGGSDQGDpGIFVSEVLPGGAAEAGGLKVGDRILSINGQDVENMTHEEAVLALKGSGGKV 76

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 57012340    816 LVRVRKSAATLGIAIEGGANTRQPLpRIVTIQRGGSAHNCGqLKVGHVILEVNGQTLRGKEHKEAARIIAEA 887
Cdd:smart00228   4 LVELEKGGGGLGFSLVGGKDEGGGV-VVSSVVPGSPAAKAG-LRVGDVILEVNGTSVEGLTHLEAVDLLKKA 73

periplasmic serine protease, Do/DeqQ family; This family consists of a set proteins various designated DegP, heat shock protein HtrA, and protease DO. The ortholog in Pseudomonas aeruginosa is designated MucD and is found in an operon that controls mucoid phenotype. This family also includes the DegQ (HhoA) paralog in E. coli which can rescue a DegP mutant, but not the smaller DegS paralog, which cannot. Members of this family are located in the periplasm and have separable functions as both protease and chaperone. Members have a trypsin domain and two copies of a PDZ domain. This protein protects bacteria from thermal and other stresses and may be important for the survival of bacterial pathogens.// The chaperone function is dominant at low temperatures, whereas the proteolytic activity is turned on at elevated temperatures. [Protein fate, Protein folding and stabilization, Protein fate, Degradation of proteins, peptides, and glycopeptides]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340   160 GSEHGVGIYVSLVEPGSLAEKEGLRVGDQILRVNDKSLARVTH-AEAVKALKGSKKLVLSVYSAGRIPGGYVTnhIYTWV 238
Cdd:TIGR02037 252 GLEKQRGALVAQVLPGSPAEKAGLKAGDVITSVNGKPISSFADlRRAIGTLKPGKKVTLGILRKGKEKTITVT--LGASP 329

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340   239 DPQGRSTSPpssLPQPHGSTLRQREDDRrstlhLLQSGDEKkvnlvlgdgrslgltirggaeyglGIYITGVDPGSEAES 318
Cdd:TIGR02037 330 EEQASSSNP---FLGLTVANLSPEIRKE-----LRLKGDVK------------------------GVVVTKVVSGSPAAR 377

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|.
gi 57012340   319 SGLKVGDQILEVNGRSFLNI--LHDeAVKLLKSSRHLILTV 357
Cdd:TIGR02037 378 AGLQPGDVILSVNQQPVSSVaeLRK-VLARAKKGGRVALLI 417

C-terminal processing protease CtpA/Prc, contains a PDZ domain [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 57012340 298 GAEYGL---GIYITGVDPGSEAESSGLKVGDQILEVNGRSFLNILHDEAVKLLK 348
Cdd:COG0793  63 GAELGEedgKVVVVSVIPGSPAEKAGIKPGDIILAIDGKSVAGLTLDDAVKLLR 116

serine endoprotease DegS;

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 57012340  158 RGGSEHGVGIYVSLVEPGSLAEKEGLRVGDQILRVNDK 195
Cdd:PRK10898 272 GGGIDQLQGIVVNEVSPDGPAAKAGIQVNDLIISVNNK 309

PDZ domain 2 of the full-length isoform of whirlin and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of the full-length isoform of whirlin and related domains. Whirlin is an essential protein for developmental pathways in photoreceptor cells of the retina and hair cells of the inner ear. The full-length whirlin isoform has two harmonin N-like domains, three PDZ domains, a proline-rich region, and a PDZ-binding motif. Whirlin isoforms may form different complexes at the periciliary membrane complex (PMC) in photoreceptors, and the stereociliary tip and base in inner ear hair cells. It interacts with ADGRV1 and usherin at the PMC; with SANS and RpgrORF15 at the connecting cilium in photoreceptors; with EPS8, MYO15A, p55, and CASK proteins at the stereociliary tip of inner ear hair cells; and with ADGRV1, usherin, and PDZD7 at the stereociliary base in inner ear hair cells. Mutations in the gene encoding whirlin (WHRN; also known as USH2D and DFNB31), have been found to cause either USH2 subtype (USH2D) or autosomal recessive non-syndromic deafness type 31 (DFNB31). Whirlin is the key protein in the USH2 complex (whirlin, usherin and GPR98) which recruits other USH2 causative proteins at the periciliary membrane in photoreceptors and the ankle link of the stereocilia in hair cells. Whirlin's interaction with espin, another stereociliary protein, may be important for the architecture of the USH2 complex. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This whirlin family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 278 EKKVNLVLGDGRSLGLTIRGGAEYGLGIYITGVDPGSEAESSGLKVGDQILEVNGRSFLNILHDEAVKLLKSSRHLILTV 357
Cdd:cd06741   1 ERKVNLVVEDGQSLGLMIRGGAEYGLGIYVTGVDPGSVAENAGLKVGDQILEVNGRSFLDITHDEAVKILKSSKHLIMTV 80

                ....
gi 57012340 358 KDVG 361
Cdd:cd06741  81 KDVG 84

first harmonin_N_like domain (repeat 1) of the long isoform of whirlin, and related domains; This subgroup contains the first of two harmonin_N_like domains of the long isoform of whirlin, and related domains. Whirlin is a postsynaptic density-95/discs-large/ZO-1 (PDZ) domain-containing scaffold protein which binds various components of the Usher protein network of the inner ear and the retina: erythrocyte protein p55, usherin, VlGR1, and myosin XVa. The long isoform of whirlin contains two harmonin_N_like domains, and three PDZ protein-binding domains, PDZ1-3. This first harmonin_N_like domain precedes PDZ1, and is a putative protein-binding module based on its sequence similarity to the N-terminal domain of harmonin. This first harmonin_N_like domain has been assayed for interaction with the cytoplasmic domain of cadherin 23 (a component of the Usher network and an interacting partner of the harmonin N-domain), however no interaction could be detected. The short whirlin isoform, derived from an alternative start ATG, lacks this first harmonin_N_like domain. The short isoform has in common with the long isoform, the second harmonin_N_like domain (designated repeat 2, not present in this subgroup), and PDZ3.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 57012340  38 ANVRQLHQALTALLSEPEREQFTHCLNAYHARRNVFDLVRTLRVLLDSPVKRRLLPMLRLVIPRSDQLLFDQYTAE 113
Cdd:cd07356   3 ANVRNLHVALTKLLSDAEREEFTHCLNCYHKNRNVYDLVQSLKVVLDSPEKRQLFPLLRLVIPRSDQALFDQYTSE 78

PDZ domain 2 of the canonical isoform 1 of PDZ domain containing 7 (PDZD7), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of the long isoform 1 of PDZD7, and related domains. PDZD7 is critical for the organization of Usher syndrome type 2 (USH2) complex. Usher syndrome is the leading cause of hereditary sensory deaf-blindness in humans; USH2 is the most common sub-type. Formation of the USH2 complex is based upon heterodimerization between PDZD7 and whirlin (another PDZ domain-containing protein) and a subsequent dynamic interplay between USH2 proteins via their multiple PDZ domains. The PDZD7 PDZ2 domain binds GPR98 (also known as VLGR1) and usherin (USH2A). PDZD7 and whirlin form heterodimers through their multiple PDZ domains; whirlin and PDZD7 interact with usherin and GPR98 to form an interdependent ankle link complex. PDZD7 also interacts with myosin VIIa. PDZD7 also forms homodimers through its PDZ2 domain. Various isoforms of PDZD7 produced by alternative splicing have been identified; this subgroup includes the second PDZ domain of the canonical isoform of PDZD7- isoform 1. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This PDZD7-like family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 278 EKKVNLVLG-DGRSLGLTIRGGAEYGLGIYITGVDPGSEAESSGLKVGDQILEVNGRSFLNILHDEAVKLLKSSRHLILT 356
Cdd:cd10834   1 RRIVHLYTTsDDYCLGFNIRGGSEYGLGIYVSKVDPGGLAEQNGIKVGDQILAVNGVSFEDITHSKAVEVLKSQTHLMLT 80

                ....*
gi 57012340 357 VKDVG 361
Cdd:cd10834  81 IKEVG 85

canonical PDZ domain; Canonical PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain. PDZ domains usually bind to short specific peptide sequences located at the C-terminal end of their partner proteins known as PDZ binding motifs. These domains can also interact with internal peptide motifs and certain lipids, and can take part in a head-to-tail oligomerization with other PDZ domains. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 280 KVNLVLGDGRSLGLTIRGGAEYGLGIYITGVDPGSEAESSG-LKVGDQILEVNGRSFLNILHDEAVKLLKSS-RHLILTV 357
Cdd:cd00136   1 TVTLEKDPGGGLGFSIRGGKDGGGGIFVSRVEPGGPAARDGrLRVGDRILEVNGVSLEGLTHEEAVELLKSAgGEVTLTV 80

                .
gi 57012340 358 K 358
Cdd:cd00136  81 R 81

PDZ domain 1 of the full-length isoform of whirlin and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 1 of the full-length isoform of whirlin and related domains. Whirlin is an essential protein for developmental pathways in photoreceptor cells of the retina and hair cells of the inner ear. The full-length whirlin isoform has two harmonin N-like domains, three PDZ domains, a proline-rich region, and a PDZ-binding motif. Whirlin isoforms may form different complexes at the periciliary membrane complex (PMC) in photoreceptors, and the stereociliary tip and base in inner ear hair cells. It interacts with ADGRV1 and usherin at the PMC; with SANS and RpgrORF15 at the connecting cilium in photoreceptors; with EPS8, MYO15A, p55, and CASK proteins at the stereociliary tip of inner ear hair cells; and with ADGRV1, usherin, and PDZD7 at the stereociliary base in inner ear hair cells. Mutations in the gene encoding whirlin (WHRN; also known as USH2D and DFNB31), have been found to cause either USH2 subtype (USH2D) or autosomal recessive non-syndromic deafness type 31 (DFNB31). Whirlin is the key protein in the USH2 complex (whirlin, usherin and GPR98) which recruits other USH2 causative proteins at the periciliary membrane in photoreceptors and the ankle link of the stereocilia in hair cells. Whirlin's interaction with espin, another stereociliary protein, may be important for the architecture of the USH2 complex. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This whirlin family PDZ1 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 57012340 291 LGLTIRGGAEYGLGIYITGVDPGSEAESSGLKVGDQILEVNGRSFLNILHDEAVKLLKSSRHLILTVK 358
Cdd:cd06740  15 LGFSIRGGAEHGVGIYVSLVEPGSLAEKEGLRVGDQILRVNDVSFEKVTHAEAVKILRVSKKLVLSVR 82

PDZ domain 2 of the full-length isoform of whirlin and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of the full-length isoform of whirlin and related domains. Whirlin is an essential protein for developmental pathways in photoreceptor cells of the retina and hair cells of the inner ear. The full-length whirlin isoform has two harmonin N-like domains, three PDZ domains, a proline-rich region, and a PDZ-binding motif. Whirlin isoforms may form different complexes at the periciliary membrane complex (PMC) in photoreceptors, and the stereociliary tip and base in inner ear hair cells. It interacts with ADGRV1 and usherin at the PMC; with SANS and RpgrORF15 at the connecting cilium in photoreceptors; with EPS8, MYO15A, p55, and CASK proteins at the stereociliary tip of inner ear hair cells; and with ADGRV1, usherin, and PDZD7 at the stereociliary base in inner ear hair cells. Mutations in the gene encoding whirlin (WHRN; also known as USH2D and DFNB31), have been found to cause either USH2 subtype (USH2D) or autosomal recessive non-syndromic deafness type 31 (DFNB31). Whirlin is the key protein in the USH2 complex (whirlin, usherin and GPR98) which recruits other USH2 causative proteins at the periciliary membrane in photoreceptors and the ankle link of the stereocilia in hair cells. Whirlin's interaction with espin, another stereociliary protein, may be important for the architecture of the USH2 complex. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This whirlin family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 139 VRLVSLRRAKaHEGLGFSIRGGSEHGVGIYVSLVEPGSLAEKEGLRVGDQILRVNDKSLARVTHAEAVKALKGSKKLVLS 218
Cdd:cd06741   1 ERKVNLVVED-GQSLGLMIRGGAEYGLGIYVTGVDPGSVAENAGLKVGDQILEVNGRSFLDITHDEAVKILKSSKHLIMT 79

                ....*
gi 57012340 219 VYSAG 223
Cdd:cd06741  80 VKDVG 84

PDZ domain 1 of harmonin isoforms a, b, and c, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 1 of harmonin isoforms a, b, and c, and related domains. Harmonin (also known as Usher Type 1C, PDZ-73 and AIE-75) is a key organizer of the Usher (USH) protein interactome. USH syndrome is the leading cause of hereditary sensory deaf-blindness in humans; three clinically distinct types of USH have been identified, type 1 to 3. The gene encoding harmonin (USH1C) is the causative gene for the USH type 1C phenotype. There are at least 10 alternatively spliced isoforms of harmonin, which are divided into three subclasses (a, b, and c). All isoforms contain the first two PDZ domains and the first coiled-coil domain. The a and b isoforms all have a third PDZ domain. The different PDZ domains are responsible for interactions with all known Usher syndrome type 1 proteins, and most Usher syndrome type 2 proteins. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This harmonin family PDZ1 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 139 VRLVSLRRAKAhEGLGFSIRGGSEHGVGIYVSLVEPGSLAEKEGLRVGDQILRVNDKSLARVTHAEAVKALKGSKKLVLS 218
Cdd:cd06737   2 LRLVRLDRRGP-ESLGFSVRGGLEHGCGLFVSHVSPGSQADNKGLRVGDEIVRINGYSISQCTHEEVINLIKTKKTVSLK 80

                ....*
gi 57012340 219 VYSAG 223
Cdd:cd06737  81 VRHVG 85

N-terminal protein-binding module of harmonin and similar domains, also known as HHD (harmonin homology domain); This domain is found in harmonin, and similar proteins such as delphilin, and whirlin. These are postsynaptic density-95/discs-large/ZO-1 (PDZ) domain-containing scaffold proteins. Harmonin and whirlin are organizers of the Usher protein network of the inner ear and the retina, delphilin is found at the cerebellar parallel fiber-Purkinje cell synapses. This domain is also found in CCM2 (also called malcavernin; C7orf22/chromosome 7 open reading frame 22; OSM). CCM2 along with CCM1 and CCM3 constitutes a set of proteins which when mutated are responsible for cerebral cavernous malformations, an autosomal dominant neurovascular disease characterized by cerebral hemorrhages and vascular malformations in the central nervous system. CCM2 plays many functional roles. CCM2 functions as a scaffold involved in small GTPase Rac-dependent p38 mitogen-activated protein kinase (MAPK) activation when the cell is under hyperosmotic stress. It associates with CCM1 in the signaling cascades that regulate vascular integrity and participates in HEG1 (the transmembrane receptor heart of glass 1) mediated endothelial cell junctions. CCM proteins also inhibit the activation of small GTPase RhoA and its downstream effector Rho kinase (ROCK) to limit vascular permeability. CCM2 mediates TrkA-dependent cell death via its N-terminal PTB domain in pediatric neuroblastic tumours; the C-terminal domain of malcavernin represented here has also been refered to as the Karet domain. Harmonin contains a single copy of this domain at its N-terminus which binds specifically to a short internal peptide fragment of the cadherin 23 cytoplasmic domain (a component of the Usher protein network). Whirlin contains two copies of this domain; the first of these has been assayed for interaction with the cytoplasmic domain of cadherin 23 and no interaction could be detected.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 57012340 420 GNQTRALLDDQARHLLTEQERATMMYYLAQYRGGTiSVEAMVMALFELLNTHAKFSLLSEVRSIISPQDLDRFDHLVLR 498
Cdd:cd07347   1 RRELARLFSEQADQLLTDQERAYVTQALSEYRKGR-SVEALVADLFPVLDTPAKLSLLQGLRSLIPPKDQQRFDELVAQ 78

PDZ domain of Rap guanine nucleotide exchange factor 2 and Rap guanine nucleotide exchange factor 6, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of Rap guanine nucleotide exchange factor 2 (RapGEF2, also named RA-GEF-1, PDZ-GEF1, CNrasGEF and nRapGEP) and Rap guanine nucleotide exchange factor 6 (RapGEF6, also named RA-GEF-2 and PDZ-GEF2). RapGEF2 and RapGEF6 constitute a subfamily of guanine nucleotide exchange factors (GEFs) for RAP small GTPases that is characterized by the possession of the PDZ and Ras/Rap-associating domains. They activate Rap small GTPases, by catalyzing the release of GDP from the inactive GDP-bound forms, thereby accelerating GTP loading to yield the active GTP-bound forms. The PDZ domain of RapGEF6 (also known as PDZ-GEF2) binds junctional adhesion molecule A (JAM-A). PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This RapGEF2 and RapGEF6 family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 140 RLVSLRRAKAHEGLGFSIRGGSEHGVGIYVSLVEPGSLAEKEGLRVGDQILRVNDKSLARVTHAEAVKALKGSKKLVLSV 219
Cdd:cd06755   1 RTVTLTRPSRESPLHFSLLGGSEKGFGIFVSKVEKGSKAAEAGLKRGDQILEVNGQNFENITLKKALEILRNNTHLSITV 80

                ..
gi 57012340 220 YS 221
Cdd:cd06755  81 KT 82

PDZ domain 1 of harmonin isoforms a, b, and c, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 1 of harmonin isoforms a, b, and c, and related domains. Harmonin (also known as Usher Type 1C, PDZ-73 and AIE-75) is a key organizer of the Usher (USH) protein interactome. USH syndrome is the leading cause of hereditary sensory deaf-blindness in humans; three clinically distinct types of USH have been identified, type 1 to 3. The gene encoding harmonin (USH1C) is the causative gene for the USH type 1C phenotype. There are at least 10 alternatively spliced isoforms of harmonin, which are divided into three subclasses (a, b, and c). All isoforms contain the first two PDZ domains and the first coiled-coil domain. The a and b isoforms all have a third PDZ domain. The different PDZ domains are responsible for interactions with all known Usher syndrome type 1 proteins, and most Usher syndrome type 2 proteins. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This harmonin family PDZ1 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 280 KVNLVLGDGR---SLGLTIRGGAEYGLGIYITGVDPGSEAESSGLKVGDQILEVNGRSFLNILHDEAVKLLKSSRHLILT 356
Cdd:cd06737   1 KLRLVRLDRRgpeSLGFSVRGGLEHGCGLFVSHVSPGSQADNKGLRVGDEIVRINGYSISQCTHEEVINLIKTKKTVSLK 80

                ....*
gi 57012340 357 VKDVG 361
Cdd:cd06737  81 VRHVG 85

PDZ domain 2 of harmonin isoforms a, b, and c, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of harmonin isoforms a, b, and c, and related domains. Harmonin (also known as Usher Type 1C, PDZ-73 and AIE-75) is a key organizer of the Usher (USH) protein interactome. USH syndrome is the leading cause of hereditary sensory deaf-blindness in humans; three clinically distinct types of USH have been identified, type 1 to 3. The gene encoding harmonin (USH1C) is the causative gene for the USH type 1C phenotype. There are at least 10 alternatively spliced isoforms of harmonin, which are divided into three subclasses (a, b, and c). All isoforms contain the first two PDZ domains and the first coiled-coil domain. The a and b isoforms all have a third PDZ domain. The different PDZ domains are responsible for interactions with all known Usher syndrome type 1 proteins, and most Usher syndrome type 2 proteins. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This harmonin family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 57012340 152 GLGFSIRGGSEHGVGIYVSLVEPGSLAEKEGLRVGDQILRVNDKSLARVTHAEAVKALKGSKKLVLSV 219
Cdd:cd06738  14 GLGCSISSGPTQKPGIFISNVKPGSLAEEVGLEVGDQIVEVNGTSFTNVDHKEAVMALKSSRHLTITV 81

PDZ domain of syntrophins, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of syntrophins (including alpha-1-syntrophin, beta-1-syntrophin, beta-2-syntrophin, gamma-1-syntrophin, and gamma-2-syntrophin), and related domains. Syntrophins play a role in recruiting various signaling molecules into signaling complexes and help provide appropriate spatiotemporal regulation of signaling pathways. They function in cytoskeletal organization and maintenance; as components of the dystrophin-glycoprotein complex (DGC), they help maintain structural integrity of skeletal muscle fibers. They link voltage-gated sodium channels to the actin cytoskeleton and the extracellular matrix, and control the localization and activity of the actin reorganizing proteins such as PI3K, PI(3,4)P2 and TAPP1. Through association with various cytoskeletal proteins within the cells, they are involved in processes such as regulation of focal adhesions, myogenesis, calcium homeostasis, and cell migration. They also have roles in synapse formation and in the organization of utrophin, acetylcholine receptor, and acetylcholinesterase at the neuromuscular synapse. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This syntrophin-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 57012340 140 RLVSLRRAKAHeGLGFSIRGGSEHGVGIYVSLVEPGSLAEKEG-LRVGDQILRVNDKSLARVTHAEAVKALKGSKKLVL 217
Cdd:cd06801   1 RTVRVVKQDVG-GLGISIKGGAEHKMPILISKIFKGQAADQTGqLFVGDAILSVNGENLEDATHDEAVQALKNAGDEVT 78

PDZ domain; PDZ domains are found in diverse signaling proteins.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 57012340   141 LVSLRRAKaHEGLGFSIRGGSEHGV-GIYVSLVEPGSLAEKEGLRVGDQILRVNDKSLARVTHAEAVKALKGSKKLV 216
Cdd:pfam00595   1 QVTLEKDG-RGGLGFSLKGGSDQGDpGIFVSEVLPGGAAEAGGLKVGDRILSINGQDVENMTHEEAVLALKGSGGKV 76

N-terminal protein-binding module of harmonin and similar domains, also known as HHD (harmonin homology domain); This domain is found in harmonin, and similar proteins such as delphilin, and whirlin. These are postsynaptic density-95/discs-large/ZO-1 (PDZ) domain-containing scaffold proteins. Harmonin and whirlin are organizers of the Usher protein network of the inner ear and the retina, delphilin is found at the cerebellar parallel fiber-Purkinje cell synapses. This domain is also found in CCM2 (also called malcavernin; C7orf22/chromosome 7 open reading frame 22; OSM). CCM2 along with CCM1 and CCM3 constitutes a set of proteins which when mutated are responsible for cerebral cavernous malformations, an autosomal dominant neurovascular disease characterized by cerebral hemorrhages and vascular malformations in the central nervous system. CCM2 plays many functional roles. CCM2 functions as a scaffold involved in small GTPase Rac-dependent p38 mitogen-activated protein kinase (MAPK) activation when the cell is under hyperosmotic stress. It associates with CCM1 in the signaling cascades that regulate vascular integrity and participates in HEG1 (the transmembrane receptor heart of glass 1) mediated endothelial cell junctions. CCM proteins also inhibit the activation of small GTPase RhoA and its downstream effector Rho kinase (ROCK) to limit vascular permeability. CCM2 mediates TrkA-dependent cell death via its N-terminal PTB domain in pediatric neuroblastic tumours; the C-terminal domain of malcavernin represented here has also been refered to as the Karet domain. Harmonin contains a single copy of this domain at its N-terminus which binds specifically to a short internal peptide fragment of the cadherin 23 cytoplasmic domain (a component of the Usher protein network). Whirlin contains two copies of this domain; the first of these has been assayed for interaction with the cytoplasmic domain of cadherin 23 and no interaction could be detected.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 57012340  40 VRQLHQALTALLSEPEREQFTHCLNAYHARRNVFDLVRTLRVLLDSPVKRRLLPMLRLVIPRSDQLLFDQYTA 112
Cdd:cd07347   5 ARLFSEQADQLLTDQERAYVTQALSEYRKGRSVEALVADLFPVLDTPAKLSLLQGLRSLIPPKDQQRFDELVA 77

PDZ domain 3 of human discs large homolog 1 (Dlg1), Dlg2, and Dlg4, Drosophila disc large (Dlg), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 3 of Drosophila Dlg1, human Dlg1, 2, and 4 and related domains. Dlg1 (also known as synapse-associated protein Dlg197; SAP-97), Dlg2 (also known as channel-associated protein of synapse-110; postsynaptic density protein 93, PSD-93), Dlg4 (also known as postsynaptic density protein 95, PSD-95; synapse-associated protein 90, SAP-90) each have 3 PDZ domains and belong to the membrane-associated guanylate kinase family. Dlg1 regulates antigen receptor signaling and cell polarity in lymphocytes, B-cell proliferation and antibody production, and TGFalpha bioavailability; its PDZ3 domain binds pro-TGFalpha, and its PDZ2 domain binds the TACE metalloprotease responsible for cleaving pro-TGFalpha to a soluble form. Dlg2 is involved in N-methyl-D-aspartate (NMDA) receptor signaling, regulating surface expression of NMDA receptors in dorsal horn neurons of the spinal cord; it interacts with NMDA receptor subunits and with Shaker-type K+ channel subunits to cluster into a channel complex. The Dlg4 PDZ1 domain binds NMDA receptors, and its PDZ2 domain binds neuronal nitric oxide synthase (nNOS), forming a complex in neurons. The Drosophila Scribble complex (Scribble, Dlg, and lethal giant larvae) plays a role in apico-basal cell polarity, and in other forms of polarity, including regulation of the actin cytoskeleton, cell signaling and vesicular trafficking, and in tumor development; postsynaptic targeting of Drosophila DLG requires interactions mediated by the first two PDZ domains. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This Dlg-like family PDZ3 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 138 EVRLVSLRRAKAheGLGFSIRGGsEHGVGIYVSLVEPGSLAEKEG-LRVGDQILRVNDKSLARVTHAEAVKALKGSKKLV 216
Cdd:cd06795   1 EPRKIVLHKGST--GLGFNIVGG-EDGEGIFISFILAGGPADLSGeLRRGDQILSVNGVDLRNATHEQAAAALKNAGQTV 77

PDZ domain 3 of Zonula Occludens-1 (ZO-1), homologs ZO-2 and ZO-3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 3 of ZO-1, -2, -3 and related domains. Zonula occludens proteins (ZO-1, ZO-2, ZO-3) are multi-PDZ domain proteins involved in the maintenance and biogenesis of multi-protein networks at the cytoplasmic surface of intercellular contacts in epithelial and endothelial cells. They have three N-terminal PDZ domains, PDZ1-3, followed by a Src homology-3 (SH3) domain and a guanylate kinase (GuK)-like domain. Among protein-protein interactions for all ZO proteins is the binding of the first PDZ domain (PDZ1) to the C-termini of claudins , and the homo- and hetero-dimerization of ZO-proteins via their second PDZ domain (PDZ2), which takes place by symmetrical domain swapping of the first two beta-strands of PDZ2. At the cell level, ZO-1 and ZO-2 are involved in polarity maintenance, gene transcription, cell proliferation, and tumor cell metastasis. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This ZO family PDZ3 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 288 GRSLGLTIRGGAEygLGIYITGVDPGSEAESSGLKVGDQILEVNGRSFLNILHDEAVKLL 347
Cdd:cd06729  10 GGSVGLRLAGGND--VGIFVAGVQEGSPAEKQGLQEGDQILKVNGVDFRNLTREEAVLFL 67

canonical PDZ domain; Canonical PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain. PDZ domains usually bind to short specific peptide sequences located at the C-terminal end of their partner proteins known as PDZ binding motifs. These domains can also interact with internal peptide motifs and certain lipids, and can take part in a head-to-tail oligomerization with other PDZ domains. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 57012340 815 TLVRVRKSAATLGIAIEGGANTRQPLpRIVTIQRGGSAHNCGQLKVGHVILEVNGQTLRGKEHKEAARIIAEAFKT 890
Cdd:cd00136   1 TVTLEKDPGGGLGFSIRGGKDGGGGI-FVSRVEPGGPAARDGRLRVGDRILEVNGVSLEGLTHEEAVELLKSAGGE 75

PDZ domain 2 of human discs large homolog 1 (Dlg1), Dlg2, and Dlg4, Drosophila disc large (Dlg), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 1 of Drosophila Dlg1, human Dlg1,2, and 4 and related domains. Dlg1 (also known as synapse-associated protein Dlg197 or SAP-97), Dlg2 (also known as channel-associated protein of synapse-110, postsynaptic density protein 93, or PSD-93), Dlg4 (also known as postsynaptic density protein 95, PSD-95, synapse-associated protein 90, or SAP-90) each have 3 PDZ domains and belong to the membrane-associated guanylate kinase family. Dlg1 regulates antigen receptor signaling and cell polarity in lymphocytes, B-cell proliferation and antibody production, and TGFalpha bioavailability; its PDZ3 domain binds pro-TGFalpha, and its PDZ2 domain binds the TACE metalloprotease responsible for cleaving pro-TGFalpha to a soluble form. Dlg2 is involved in N-methyl-D-aspartate (NMDA) receptor signaling. It regulates surface expression of NMDA receptors in dorsal horn neurons of the spinal cord, and it also interacts with NMDA receptor subunits and with Shaker-type K+ channel subunits to cluster into a channel complex. Dlg4 PDZ1 domain binds NMDA receptors, and its PDZ2 domain binds neuronal nitric oxide synthase (nNOS), forming a complex in neurons. The Drosophila Scribble complex (Scribble, Dlg, and lethal giant larvae) plays a role in apico-basal cell polarity, and in other forms of polarity, including regulation of the actin cytoskeleton, cell signaling and vesicular trafficking, and in tumor development. Postsynaptic targeting of Drosophila DLG requires interactions mediated by the first two PDZ domains. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This Dlg-like family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 138 EVRLVslrraKAHEGLGFSIRGG--SEH---GVGIYVSLVEPGSLAEKEG-LRVGDQILRVNDKSLARVTHAEAVKALKG 211
Cdd:cd06724   1 EIKLV-----KGPKGLGFSIAGGvgNQHipgDNGIYVTKIIEGGAAQKDGrLQVGDKLLAVNDVSLEEVTHEEAVAALKN 75

                ....*
gi 57012340 212 SKKLV 216
Cdd:cd06724  76 TSDVV 80

PDZ domain 13 of multi-PDZ-domain protein 1 (MUPP1) and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 13 of MUPP1. MUPP1 and PATJ serve as scaffolding proteins linking different proteins and protein complexes involved in the organization of tight junctions and epithelial polarity. MUPP1 contains an L27 (Lin-2 and Lin-7 binding) domain and 13 PDZ domains. PATJ (also known as INAD-like) contains an L27 domain and ten PDZ domains. PATJ lacks 3 PDZ domains seen in MUPP1: PDZ6, PDZ9, and PDZ13. This MuPP1-like PDZ13 domain is therefore absent from PATJ. MUPP1 and PATJ share several binding partners, including junctional adhesion molecules (JAM), zonula occludens (ZO)-3, Pals1 (protein associated with Lin-7), Par (partitioning defective)-6 proteins, and nectins (adherence junction adhesion molecules). PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This MUPP1-like family PDZ13 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 142 VSLRRAKahEGLGFSIRGG--SEHG-VGIYVSLVEPGSLAEKEG-LRVGDQILRVNDKSLARVTHAEAVKALKGSK-KLV 216
Cdd:cd06676   2 ITLERGS--DGLGFSIVGGfgSPHGdLPIYVKTVFEKGAAAEDGrLKRGDQILAVNGESLEGVTHEEAVNILKKTKgTVT 79

                ...
gi 57012340 217 LSV 219
Cdd:cd06676  80 LTV 82

PDZ domain 5 of Danio rerio tyrosine-protein phosphatase non-receptor type 13 (Ptpn13) and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 5 of Danio rerio Ptpn13, and related domains. Protein-tyrosine phosphatases (PTPs) dephosphorylate phosphotyrosyl residues in proteins that are phosphorylated by protein tyrosine kinases (PTKs). Danio rerio Ptpn13 is a classical non-receptor-like PTP. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This PTPN13-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 57012340 149 AHEGLGFSIRGGsEHGVGIYVSLVEPGSLAEKEG-LRVGDQILRVNDKSLARVTHAEAVKALKGSKKLV 216
Cdd:cd23060   8 ANGGLGFSLVGG-EGGSGIFVKSISPGGVADRDGrLQVGDRLLQVNGESVIGLSHSKAVNILRKAKGTV 75

PDZ domain of partitioning defective 6 (Par6), Drosophila Rho GTPase-activating protein 100F (RhoGAP100F), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of Par6 (also known as PAR6 or Par-6), RhoGAP100F, and related domains. Par6 is part of a conserved machinery that directs metazoan cell polarity, a process necessary for the function of diverse cell types. Par6 forms a cell polarity-regulatory complex with atypical protein kinase C (aPKC) and Par3. Par6 can also directly associate with PALS1 (proteins associated with Lin7, also known as Stardust) providing a link between the Par3/aPKC/Par6 complex and the PALS1-PATJ (protein-associated TJ) complex. Binding partners of the Par6-PDZ domain include Par3, PALS1/Stardust; leucine-rich repeat-containing protein netrin-G ligand-2 (NGL-2), human crumbs (CRB3) involve in the morphogenesis of the tight junctions in mammalian epithelial cells, and PAR-6 co-operates with the Par6 semi-CRIB domain to bind CDC42. CDC42 regulates the Par6 PDZ domain through an allosteric CRIB-PDZ transition. Drosophila RhoGAP100F, also known as synapse defective protein 1 homolog (syd-1 homolog), is a GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound form. The RhoGAP100F-PDZ domain binds the neurexin C terminus to control synapse formation at the Drosophila neuromuscular junction. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This Par6-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57012340 279 KKVNLVLGDGRSLGLTIRGGA--EYGLGIYITGVDPGSEAESSG-LKVGDQILEVNGRSFLNILHDEAVKLLKSSRHLIL 355
Cdd:cd06718   1 RRVELIKPPGKPLGFYIRDGNgvERVPGIFISRLVLGSLADSTGlLAVGDEILEVNGVEVTGKSLDDVTDMMVAPTRLII 80

                ...
gi 57012340 356 TVK 358
Cdd:cd06718  81 TVK 83

PDZ domain 3 of the canonical isoform 1 of PDZ domain containing 7 (PDZD7), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 3 of the long isoform 1 of PDZD7, and related domains. PDZD7 is critical for the organization of the Usher syndrome type 2 (USH2) complex. Usher syndrome is the leading cause of hereditary sensory deaf-blindness in humans; USH2 is the most common sub-type. Formation of the USH2 complex is based upon heterodimerization between PDZD7 and whirlin (another PDZ domain-containing protein) and a subsequent dynamic interplay between USH2 proteins via their multiple PDZ domains. The PDZD7 PDZ2 domain binds GPR98 (also known as VLGR1) and usherin (USH2A). PDZD7 and whirlin form heterodimers through their multiple PDZ domains; whirlin and PDZD7 interact with usherin and GPR98 to form an interdependent ankle link complex. PDZD7 also interacts with myosin VIIa and can also form homodimers through its PDZ2 domain. Various isoforms of PDZD7 produced by alternative splicing have been identified; this subgroup includes the third PDZ domain of the canonical isoform of PDZD7- isoform 1. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This PDZD7-like family PDZ3 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

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gi 57012340 817 VRVRKSAATLGIAIEGGANTR-QPLPRIVTIQRGGSAHNCGQLKVGHVILEVNGQTLRGKEHKEAARIIAEAFKTKERDY 895
Cdd:cd06751   4 VELSKMKQSLGISISGGIESKvQPVVKIEKIFPGGAAALSGNLKAGYELVSVDGESLQQVTHQQAVDIIRRAYSNKSKEP 83

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gi 57012340 896 IDFLV 900
Cdd:cd06751  84 MEIVV 88

PDZ domain 2 of PDZ domain containing 2 (PDZD2), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of PDZD2, also known as KIAA0300, PIN-1, activated in prostate cancer (AIPC) and PDZ domain-containing protein 3 (PDZK3). PDZD2 has seven PDZ domains, and is expressed at exceptionally high levels in the pancreas and certain cancer tissues such as prostate cancer. It promotes the proliferation of insulinoma cells and is upregulated during prostate tumorigenesis. In osteosarcoma (OS), the microRNA miR-363 acts as a tumor suppressor by inhibiting PDZD2. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This PDZD2-like family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

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gi 57012340 279 KKVNLVLGDGrSLGLTIRGG--AEYG-LGIYITGVDPGSEAESSG-LKVGDQILEVNGRSFLNILHDEAVKLLKSSRHLI 354
Cdd:cd06758   3 WKMHLLKEKG-GLGIQITGGkgSKRGdIGIFVAGVEEGGSADRDGrLKKGDELLMINGQSLIGLSHQEAVAILRSSASPV 81

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gi 57012340 355 LTV 357
Cdd:cd06758  82 QLV 84

PDZ domain 1 of protein tyrosine phosphatase non-receptor type 13 (PTPN13),FERM and PDZ domain-containing protein 2 (FRMPD2), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 1 of PTPN13 [also known as Fas-associated protein-tyrosine phosphatase 1 (FAP-1), protein-tyrosine phosphatase 1E (PTP-E1), and protein-tyrosine phosphatase (PTPL1)], FRMPD2 (also known as PDZ domain-containing protein 4; PDZ domain-containing protein 5C), and related domains. PTPN13 regulates negative apoptotic signaling and mediates phosphoinositide 3-kinase (PI3K) signaling. PTPN13 has five PDZ domains. Proteins known to interact with PTPN13 PDZ domains include: PLEKHA1 and PLEKHA2 via PTPN13-PDZ domain 1, Fas receptor and thyroid receptor-interacting protein 6 via PTPN13-PDZ domain 2, nerve growth factor receptor and protein kinase N2 via PTPN13-PDZ domain 3, PDZ and LIM domain 4 (PDLIM4) via PTPN13-PDZ domains 2 and 4, and brain calpain-2 via PTPN13-PDZ domains 3, 4 and 5. Calpain-2-mediated PTPN13 fragments may be involved in abnormal tau aggregation and increased risk for Alzheimer's disease. FRMPD2 is localized in the basolateral membranes of polarized epithelial cells and is associated with tight junction formation and immune response; it contains 3 PDZ domains. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This PTPN13 family PDZ1 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

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gi 57012340 138 EVRLVSLRRaKAHEGLGFSIRGGSEHG---VGIYVSLVEPGSLAEKEG-LRVGDQILRVNDKSLARVTHAEAVKALKGSK 213
Cdd:cd06694   1 EIVIVTLKK-DPQKGLGFTIVGGENSGsldLGIFVKSIIPGGPADKDGrIKPGDRIIAINGQSLEGKTHHAAVEIIQNAP 79