first ubiquitin-like (Ubl) domain located at the N-terminus of coronavirus SARS-CoV non-structural protein 3 (Nsp3) and related proteins; This ubiquitin-like (Ubl) domain (Ubl1) is found at the N-terminus of coronavirus Nsp3, a large multi-functional multi-domain protein which is an essential component of the replication/transcription complex (RTC). The functions of Ubl1 in CoVs are related to single-stranded RNA (ssRNA) binding and to interacting with the nucleocapsid (N) protein. SARS-CoV Ubl1 has been shown to bind ssRNA having AUA patterns, and since the 5'-UTR of the SARS-CoV genome has a number of AUA repeats, it may bind there. In mouse hepatitis virus (MHV), this Ubl1 domain binds the cognate N protein. Adjacent to Ubl1 is a Glu-rich acidic region (also referred to as hypervariable region, HVR); Ubl1 together with HVR has been called Nsp3a. Currently, the function of HVR in CoVs is unknown. This model corresponds to one of two Ubl domains in Nsp3; the other is located N-terminal to the papain-like protease (PLpro) and is not represented by this model.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  990 PFSIPVHFANGTYQVVGFDGSSTVDEFLQRLNQETGMRKPSQSGFALFTDDPSGRDLEHCLQGRVKICDAISKWEQTLKE 1069
Cdd:cd17178     1 PFSIPVHFMNGTYQVVGFDGSTTVDEFLQTLNQETGMRKPSHSGFALFTDDPSGKDLEHCLQGSVKICDVISKWEQALKE 80

                          90       100
                  ....*....|....*....|....*..
gi 256818761 1070 LHPGKSEgGTRVVKLMYKNRLYFRSQV 1096
Cdd:cd17178    81 LHPGKYE-GTRTVRLTYKSRLYFRAQA 106

Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) members 1 and 2 (PLEKHH1) PH domain, repeat 1; PLEKHH1 and PLEKHH2 (also called PLEKHH1L) are thought to function in phospholipid binding and signal transduction. There are 3 Human PLEKHH genes: PLEKHH1, PLEKHH2, and PLEKHH3. There are many isoforms, the longest of which contain a FERM domain, a MyTH4 domain, two PH domains, a peroximal domain, a vacuolar domain, and a coiled coil stretch. The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  575 KSGYLLKMGSRVKTWKRRWFVLRQGQILYYKSPSDVIRKPQGQVDLNSHCQIVREEEAQTFQLISGNKTYYLTAESPSLL 654
Cdd:cd13282     1 KAGYLTKLGGKVKTWKRRWFVLKNGELFYYKSPNDVIRKPQGQIALDGSCEIARAEGAQTFEIVTEKRTYYLTADSENDL 80

                          90
                  ....*....|....*.
gi 256818761  655 EEWIRVLQSLLKVQVT 670
Cdd:cd13282    81 DEWIRVIQNVLRRQAS 96

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761    993 IPVHFANGTYQVVGFDGSSTVDEFLQRLNQETGMRkpSQSGFALFTDDPSGrDLEHCLQGRVKICDAISKWEQtlkelhp 1072
Cdd:smart00295    2 LKVYLLDGTTLEFEVDSSTTAEELLETVCRKLGIR--ESEYFGLQFEDPDE-DLRHWLDPAKTLLDQDVKSEP------- 71

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761   1073 gkseggtrvVKLMYKNRLYFRSQVKGETERERL-LLAFQASGEIVAGRFPVTKELALEMAALMAQVEYGDlekptlpgpg 1151
Cdd:smart00295   72 ---------LTLYFRVKFYPPDPNQLKEDPTRLnLLYLQVRNDILEGRLPCPEEEALLLAALALQAEFGD---------- 132

                           170       180       190       200       210       220       230
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 256818761   1152 gTPPTKAQHLLQQVLDRFYPRRYRNGAPPEQLRhlaDMMATKWAALQGCSPPECIRIYLTVARKWPLFGAKLF 1224
Cdd:smart00295  133 -YDEELHDLRGELSLKRFLPKQLLDSRKLKEWR---ERIVELHKELIGLSPEEAKLKYLELARKLPTYGVELF 201

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761    682 PTVKGWLTKVKHGHS---KLVWCALVGKTFYYYRSHEDK---RPLGCLPVQDAHIEEVDRSCDSDEDYeaggtgrllssh 755
Cdd:smart00233    1 VIKEGWLYKKSGGGKkswKKRYFVLFNSTLLYYKSKKDKksyKPKGSIDLSGCTVREAPDPDSSKKPH------------ 68

                            90       100       110
                    ....*....|....*....|....*....|
gi 256818761    756 cTLVIHPPEHSPTYLLIGTKHEKDTWLYHL 785
Cdd:smart00233   69 -CFEIKTSDRKTLLLQAESEEEREKWVEAL 97

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in pleckstrin homology domain-containing family H member 1 (PLEKHH1); PLEKHH1 is a homolog of Caenorhabditis elegans MAX-1 that has been implicated in motor neuron axon guidance. PLEKHH1 is critical in vascular patterning in vertebrate species through acting upstream of the ephrin pathway. PLEKHH1 contains a putative alpha-helical coiled-coil segment within the N-terminal half, and two Pleckstrin homology (PH) domains, a MyTH4 domain, and a FERM (Band 4.1, ezrin, radixin, moesin) domain within the C-terminal half. The FERM domain is made up of three sub-domains, F1, F2, and F3. The family corresponds to F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  990 PFSIPVHFANGTYQVVGFDGSSTVDEFLQRLNQETGMRKPSQSGFALFTDDPSGRDLEHCLQGRVKICDAISKWEQTLKE 1069
Cdd:cd17178     1 PFSIPVHFMNGTYQVVGFDGSTTVDEFLQTLNQETGMRKPSHSGFALFTDDPSGKDLEHCLQGSVKICDVISKWEQALKE 80

                          90       100
                  ....*....|....*....|....*..
gi 256818761 1070 LHPGKSEgGTRVVKLMYKNRLYFRSQV 1096
Cdd:cd17178    81 LHPGKYE-GTRTVRLTYKSRLYFRAQA 106

Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) members 1 and 2 (PLEKHH1) PH domain, repeat 1; PLEKHH1 and PLEKHH2 (also called PLEKHH1L) are thought to function in phospholipid binding and signal transduction. There are 3 Human PLEKHH genes: PLEKHH1, PLEKHH2, and PLEKHH3. There are many isoforms, the longest of which contain a FERM domain, a MyTH4 domain, two PH domains, a peroximal domain, a vacuolar domain, and a coiled coil stretch. The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  575 KSGYLLKMGSRVKTWKRRWFVLRQGQILYYKSPSDVIRKPQGQVDLNSHCQIVREEEAQTFQLISGNKTYYLTAESPSLL 654
Cdd:cd13282     1 KAGYLTKLGGKVKTWKRRWFVLKNGELFYYKSPNDVIRKPQGQIALDGSCEIARAEGAQTFEIVTEKRTYYLTADSENDL 80

                          90
                  ....*....|....*.
gi 256818761  655 EEWIRVLQSLLKVQVT 670
Cdd:cd13282    81 DEWIRVIQNVLRRQAS 96

MyTH4 domain; Domain in myosin and kinesin tails, present twice in myosin-VIIa, and also present in 3 other myosins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761   874 AQTALQVCLVHPELQSEIYCQLMKQIScRPPQKYSLMQCWQLLALCAPLFLPQHHFLWYVKQQLQRHADPRS-ETGQYAI 952
Cdd:pfam00784    1 AQNILQKGLKRPELRDEIYCQLIKQTT-NNPKPESLLRGWQLLALCLGTFPPSKKLLKYLLKFLKRHADDPSrEVGKYAQ 79

                           90       100
                   ....*....|....*....|....*.
gi 256818761   953 YCQRAVERTLQTGEREARPSRMEVVS 978
Cdd:pfam00784   80 FCLKRLKRTLKNGGRKYPPSREEIEA 105

FERM central domain; This domain is the central structural domain of the FERM domain.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  1099 ETERERLLLAFQASGEIVAGRFPVTKELALEMAALMAQVEYGDLEKPTlpgpggtpptkaQHLLQQVLDRFYPRRYRNGA 1178
Cdd:pfam00373    7 QDEVTRHLLYLQAKDDILEGRLPCSEEEALLLAALQLQAEFGDYQPSS------------HTSEYLSLESFLPKQLLRKM 74

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 256818761  1179 PPEQLRhlaDMMATKWAALQGCSPPECIRIYLTVARKWPLFGAKLF 1224
Cdd:pfam00373   75 KSKELE---KRVLEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 117

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761   573 LEKSGYLLKMGSRVK-TWKRRWFVLRQGQILYYKSPSDVI-RKPQGQVDLnSHCQIVR------EEEAQTFQLI----SG 640
Cdd:pfam00169    1 VVKEGWLLKKGGGKKkSWKKRYFVLFDGSLLYYKDDKSGKsKEPKGSISL-SGCEVVEvvasdsPKRKFCFELRtgerTG 79

                           90       100
                   ....*....|....*....|....*.
gi 256818761   641 NKTYYLTAESPSLLEEWIRVLQSLLK 666
Cdd:pfam00169   80 KRTYLLQAESEEERKDWIKAIQSAIR 105

Predicted nucleic acid-binding protein DR0291, contains C4-type Zn-ribbon domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761   20 LETQLFRFRlqasKIRELLADKMQELEQRLLEAEQRAENAETQVGVMEEKIKLSNLKsVDSTGTLHQKYQELLRAVQGKD 99
Cdd:COG1579    15 LDSELDRLE----HRLKELPAELAELEDELAALEARLEAAKTELEDLEKEIKRLELE-IEEVEARIKKYEEQLGNVRNNK 89

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 256818761  100 ELiSQLQAQLEKQKQTRAE-EAKI--VQEKAAKIKEWVTVKLAELEMENQQLKTCNQQLVEQVAALQDALEDLR 170
Cdd:COG1579    90 EY-EALQKEIESLKRRISDlEDEIleLMERIEELEEELAELEAELAELEAELEEKKAELDEELAELEAELEELE 162

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761    682 PTVKGWLTKVKHGHS---KLVWCALVGKTFYYYRSHEDK---RPLGCLPVQDAHIEEVDRSCDSDEDYeaggtgrllssh 755
Cdd:smart00233    1 VIKEGWLYKKSGGGKkswKKRYFVLFNSTLLYYKSKKDKksyKPKGSIDLSGCTVREAPDPDSSKKPH------------ 68

                            90       100       110
                    ....*....|....*....|....*....|
gi 256818761    756 cTLVIHPPEHSPTYLLIGTKHEKDTWLYHL 785
Cdd:smart00233   69 -CFEIKTSDRKTLLLQAESEEEREKWVEAL 97

RecF/RecN/SMC N terminal domain; This domain is found at the N terminus of SMC proteins. The SMC (structural maintenance of chromosomes) superfamily proteins have ATP-binding domains at the N- and C-termini, and two extended coiled-coil domains separated by a hinge in the middle. The eukaryotic SMC proteins form two kind of heterodimers: the SMC1/SMC3 and the SMC2/SMC4 types. These heterodimers constitute an essential part of higher order complexes, which are involved in chromatin and DNA dynamics. This family also includes the RecF and RecN proteins that are involved in DNA metabolism and recombination.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761     5 KVEVASIDWQKRCLSLE-----TQLFRFRLQASK--------IRELLADKMQELEQRLLEAEQRAENAETQVGVMEEKIK 71
Cdd:pfam02463  143 KIEIIAMMKPERRLEIEeeaagSRLKRKKKEALKklieetenLAELIIDLEELKLQELKLKEQAKKALEYYQLKEKLELE 222

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761    72 LSNLKSVD---STGTLHQKYQELLRAVQGKDELISQLQAQ----LEKQKQTRAEEAKIVQEKAAKIKEwVTVKLAELEME 144
Cdd:pfam02463  223 EEYLLYLDylkLNEERIDLLQELLRDEQEEIESSKQEIEKeeekLAQVLKENKEEEKEKKLQEEELKL-LAKEEEELKSE 301

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....
gi 256818761   145 NQQLKTCNQQLVEQVAALQ------DALEDLRMTPSEELLVVPE 182
Cdd:pfam02463  302 LLKLERRKVDDEEKLKESEkekkkaEKELKKEKEEIEELEKELK 345

Rho GTPase activating protein 25 and related proteins Pleckstrin homology (PH) domain; RhoGAP25 (also called ArhGap25) like other RhoGaps are involved in cell polarity, cell morphology and cytoskeletal organization. They act as GTPase activators for the Rac-type GTPases by converting them to an inactive GDP-bound state and control actin remodeling by inactivating Rac downstream of Rho leading to suppress leading edge protrusion and promotes cell retraction to achieve cellular polarity and are able to suppress RAC1 and CDC42 activity in vitro. Overexpression of these proteins induces cell rounding with partial or complete disruption of actin stress fibers and formation of membrane ruffles, lamellipodia, and filopodia. This hierarchy contains RhoGAP22, RhoGAP24, and RhoGAP25. Members here contain an N-terminal PH domain followed by a RhoGAP domain and either a BAR or TATA Binding Protein (TBP) Associated Factor 4 (TAF4) domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  681 KPTVKGWLTK----VKHGHSKlvWCALVGKTFYYYRSHEDKRPLGCLPVQDAHIEEVDRSCDSDEDY-----EAGGTGRL 751
Cdd:cd13263     2 RPIKSGWLKKqgsiVKNWQQR--WFVLRGDQLYYYKDEDDTKPQGTIPLPGNKVKEVPFNPEEPGKFlfeiiPGGGGDRM 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 256818761  752 LSSHctlvihppehsPTYLLIGT-KHEKDTWLYHLTVAAGGS 792
Cdd:cd13263    80 TSNH-----------DSYLLMANsQAEMEEWVKVIRRVIGSP 110

Guanylate-binding protein, C-terminal domain; Guanylate-binding protein (GBP), C-terminal domain. Guanylate-binding proteins (GBPs) are synthesized after activation of the cell by interferons. The biochemical properties of GBPs are clearly different from those of Ras-like and heterotrimeric GTP-binding proteins. They bind guanine nucleotides with low affinity (micromolar range), are stable in their absence, and have a high turnover GTPase. In addition to binding GDP/GTP, they have the unique ability to bind GMP with equal affinity and hydrolyze GTP not only to GDP, but also to GMP. This C-terminal domain has been shown to mediate inhibition of endothelial cell proliferation by inflammatory cytokines.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761   37 LLADK-MQELEQRLLEAEQRAENAETQVGVMEEKIKlsnlksvdstgTLHQKYQELLRAVQgkdELISQLQAQLEKQKQT 115
Cdd:cd16269   187 LQADQaLTEKEKEIEAERAKAEAAEQERKLLEEQQR-----------ELEQKLEDQERSYE---EHLRQLKEKMEEEREN 252

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 256818761  116 RAEEAKIVQEKaakikewvtvKLAElemenqQLKTCNQQLVEQVAALQDALEDLR 170
Cdd:cd16269   253 LLKEQERALES----------KLKE------QEALLEEGFKEQAELLQEEIRSLK 291

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in pleckstrin homology domain-containing family H member 1 (PLEKHH1); PLEKHH1 is a homolog of Caenorhabditis elegans MAX-1 that has been implicated in motor neuron axon guidance. PLEKHH1 is critical in vascular patterning in vertebrate species through acting upstream of the ephrin pathway. PLEKHH1 contains a putative alpha-helical coiled-coil segment within the N-terminal half, and two Pleckstrin homology (PH) domains, a MyTH4 domain, and a FERM (Band 4.1, ezrin, radixin, moesin) domain within the C-terminal half. The FERM domain is made up of three sub-domains, F1, F2, and F3. The family corresponds to F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  990 PFSIPVHFANGTYQVVGFDGSSTVDEFLQRLNQETGMRKPSQSGFALFTDDPSGRDLEHCLQGRVKICDAISKWEQTLKE 1069
Cdd:cd17178     1 PFSIPVHFMNGTYQVVGFDGSTTVDEFLQTLNQETGMRKPSHSGFALFTDDPSGKDLEHCLQGSVKICDVISKWEQALKE 80

                          90       100
                  ....*....|....*....|....*..
gi 256818761 1070 LHPGKSEgGTRVVKLMYKNRLYFRSQV 1096
Cdd:cd17178    81 LHPGKYE-GTRTVRLTYKSRLYFRAQA 106

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in Caenorhabditis elegans max-1 and its homologs PLEKHH1 and PLEKHH2; Caenorhabditis elegans max-1 is expressed and functions in motor neurons. MAX-1 protein plays a possible role in netrin-induced axon repulsion by modulating the UNC-5 receptor signaling pathway. PLEKHH1 is critically required in vascular patterning in vertebrate species through acting upstream of the ephrin pathway. PLEKHH2 is highly enriched in renal glomerular podocytes, and acts as a novel, important component of the podocyte foot processes. It is involved in matrix adhesion and actin dynamics. Members in this family all contain two Pleckstrin homology (PH) domains, a MyTH4 domain, and a FERM (Band 4.1, ezrin, radixin, moesin) domain within the C-terminal half. The FERM domain is made up of three sub-domains, F1, F2, and F3. The family corresponds to F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  990 PFSIPVHFANGTYQVVGFDGSSTVDEFLQRLNQETGMRKPSQSGFALFTDDPSGRDLEHCLQGRVKICDAISKWEQTLKE 1069
Cdd:cd17094     1 PISIPVHLPNGTYQVVGFDGSTTVEEFLQTLNLELGIRPPSQSGFALFSDDPIGKDIEHCLQPSVKICDVISKWERASRE 80

                          90       100
                  ....*....|....*....|...
gi 256818761 1070 LHPGKSEgGTRVVKLMYKNRLYF 1092
Cdd:cd17094    81 AHSGKVD-SSRVIRLTYKNRLYF 102

Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) members 1 and 2 (PLEKHH1) PH domain, repeat 1; PLEKHH1 and PLEKHH2 (also called PLEKHH1L) are thought to function in phospholipid binding and signal transduction. There are 3 Human PLEKHH genes: PLEKHH1, PLEKHH2, and PLEKHH3. There are many isoforms, the longest of which contain a FERM domain, a MyTH4 domain, two PH domains, a peroximal domain, a vacuolar domain, and a coiled coil stretch. The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  575 KSGYLLKMGSRVKTWKRRWFVLRQGQILYYKSPSDVIRKPQGQVDLNSHCQIVREEEAQTFQLISGNKTYYLTAESPSLL 654
Cdd:cd13282     1 KAGYLTKLGGKVKTWKRRWFVLKNGELFYYKSPNDVIRKPQGQIALDGSCEIARAEGAQTFEIVTEKRTYYLTADSENDL 80

                          90
                  ....*....|....*.
gi 256818761  655 EEWIRVLQSLLKVQVT 670
Cdd:cd13282    81 DEWIRVIQNVLRRQAS 96

MyTH4 domain; Domain in myosin and kinesin tails, present twice in myosin-VIIa, and also present in 3 other myosins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761   874 AQTALQVCLVHPELQSEIYCQLMKQIScRPPQKYSLMQCWQLLALCAPLFLPQHHFLWYVKQQLQRHADPRS-ETGQYAI 952
Cdd:pfam00784    1 AQNILQKGLKRPELRDEIYCQLIKQTT-NNPKPESLLRGWQLLALCLGTFPPSKKLLKYLLKFLKRHADDPSrEVGKYAQ 79

                           90       100
                   ....*....|....*....|....*.
gi 256818761   953 YCQRAVERTLQTGEREARPSRMEVVS 978
Cdd:pfam00784   80 FCLKRLKRTLKNGGRKYPPSREEIEA 105

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  575 KSGYLLKMGSRV-KTWKRRWFVLRQGQILYYKSPSDVIRKPQGQVDLNSHCQIV---REEEAQTFQLI-SGNKTYYLTAE 649
Cdd:cd00821     1 KEGYLLKRGGGGlKSWKKRWFVLFEGVLLYYKSKKDSSYKPKGSIPLSGILEVEevsPKERPHCFELVtPDGRTYYLQAD 80

                          90
                  ....*....|..
gi 256818761  650 SPSLLEEWIRVL 661
Cdd:cd00821    81 SEEERQEWLKAL 92

Tandem PH-domain-containing protein 2 Pleckstrin homology (PH) domain; The binding of TAPP2 (also called PLEKHA2) adaptors to PtdIns(3,4)P(2), but not PI(3,4, 5)P3, function as negative regulators of insulin and PI3K signalling pathways (i.e. TAPP/utrophin/syntrophin complex). TAPP2 contains two sequential PH domains in which the C-terminal PH domain specifically binds PtdIns(3,4)P2 with high affinity. The N-terminal PH domain does not interact with any phosphoinositide tested. They also contain a C-terminal PDZ-binding motif that interacts with several PDZ-binding proteins, including PTPN13 (known previously as PTPL1 or FAP-1) as well as the scaffolding proteins MUPP1 (multiple PDZ-domain-containing protein 1), syntrophin and utrophin. The members here are most sequence similar to TAPP2 proteins, but may not be actual TAPP2 proteins. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  571 EALEKSGYLLKMGSRVKTWKRRWFVLRQGQILYYKSPSD--VIRkpqgQVDLN-----SHCQIVREEeaQTFQLISGNKT 643
Cdd:cd13255     4 EAVLKAGYLEKKGERRKTWKKRWFVLRPTKLAYYKNDKEyrLLR----LIDLTdihtcTEVQLKKHD--NTFGIVTPART 77

                          90
                  ....*....|....*...
gi 256818761  644 YYLTAESPSLLEEWIRVL 661
Cdd:cd13255    78 FYVQADSKAEMESWISAI 95

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761   573 LEKSGYLLKMGSRVK-TWKRRWFVLRQGQILYYKSPSDVI-RKPQGQVDLnSHCQIVR------EEEAQTFQLI----SG 640
Cdd:pfam00169    1 VVKEGWLLKKGGGKKkSWKKRYFVLFDGSLLYYKDDKSGKsKEPKGSISL-SGCEVVEvvasdsPKRKFCFELRtgerTG 79

                           90       100
                   ....*....|....*....|....*.
gi 256818761   641 NKTYYLTAESPSLLEEWIRVLQSLLK 666
Cdd:pfam00169   80 KRTYLLQAESEEERKDWIKAIQSAIR 105

Dual Adaptor for Phosphotyrosine and 3-Phosphoinositides Pleckstrin homology (PH) domain; DAPP1 (also known as PHISH/3' phosphoinositide-interacting SH2 domain-containing protein or Bam32) plays a role in B-cell activation and has potential roles in T-cell and mast cell function. DAPP1 promotes B cell receptor (BCR) induced activation of Rho GTPases Rac1 and Cdc42, which feed into mitogen-activated protein kinases (MAPK) activation pathways and affect cytoskeletal rearrangement. DAPP1can also regulate BCR-induced activation of extracellular signal-regulated kinase (ERK), and c-jun NH2-terminal kinase (JNK). DAPP1 contains an N-terminal SH2 domain and a C-terminal pleckstrin homology (PH) domain with a single tyrosine phosphorylation site located centrally. DAPP1 binds strongly to both PtdIns(3,4,5)P3 and PtdIns(3,4)P2. The PH domain is essential for plasma membrane recruitment of PI3K upon cell activation. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  575 KSGYLLKMGSRVKTWKRRWFVLRQGQILYYKSPSDVirKPQGQVDLNsHCQIVREEEAQ----TFQLISGNKTYYLTAES 650
Cdd:cd10573     5 KEGYLTKLGGIVKNWKTRWFVLRRNELKYFKTRGDT--KPIRVLDLR-ECSSVQRDYSQgkvnCFCLVFPERTFYMYANT 81

                          90
                  ....*....|....*
gi 256818761  651 PSLLEEWIRVLQSLL 665
Cdd:cd10573    82 EEEADEWVKLLKWKL 96

Sesquipedalian family Pleckstrin homology (PH) domain; The sesquipedalian family has 2 mammalian members: Ses1 and Ses2, which are also callled 7 kDa inositol polyphosphate phosphatase-interacting protein 1 and 2. They play a role in endocytic trafficking and are required for receptor recycling from endosomes, both to the trans-Golgi network and the plasma membrane. Members of this family form homodimers and heterodimers. Sesquipedalian interacts with inositol polyphosphate 5-phosphatase OCRL-1 (INPP5F) also known as Lowe oculocerebrorenal syndrome protein, a phosphatase enzyme that is involved in actin polymerization and is found in the trans-Golgi network and INPP5B. Sesquipedalian contains a single PH domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  566 YSTDGEALEKSGYLLKMGSRVKTWKRRWFVLRqGQIL-YYKSPSDviRKPQGQVDLNShCQIVREEEAQ--TFQLI---S 639
Cdd:cd13288     1 YATCNSPVDKEGYLWKKGERNTSYQKRWFVLK-GNLLfYFEKKGD--REPLGVIVLEG-CTVELAEDAEpyAFAIRfdgP 76

                          90       100
                  ....*....|....*....|...
gi 256818761  640 GNKTYYLTAESPSLLEEWIRVLQ 662
Cdd:cd13288    77 GARSYVLAAENQEDMESWMKALS 99

Phosphoinositol 3-phosphate binding proteins 1, 2, and 3 pleckstrin homology (PH) domain; PEPP1 (also called PLEKHA4/PH domain-containing family A member 4 and RHOXF1/Rhox homeobox family member 1), and related homologs PEPP2 (also called PLEKHA5/PH domain-containing family A member 5) and PEPP3 (also called PLEKHA6/PH domain-containing family A member 6), have PH domains that interact specifically with PtdIns(3,4)P3. Other proteins that bind PtdIns(3,4)P3 specifically are: TAPP1 (tandem PH-domain-containing protein-1) and TAPP2], PtdIns3P AtPH1, and Ptd- Ins(3,5)P2 (centaurin-beta2). All of these proteins contain at least 5 of the 6 conserved amino acids that make up the putative phosphatidylinositol 3,4,5- trisphosphate-binding motif (PPBM) located at their N-terminus. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  575 KSGYLLKM-GSRVKTWKRRWFVLRQGQILYYKSPSDviRKPQGQVDLNSHcQIvreEEAQTFQLIS----------GNKT 643
Cdd:cd13248     9 MSGWLHKQgGSGLKNWRKRWFVLKDNCLYYYKDPEE--EKALGSILLPSY-TI---SPAPPSDEISrkfafkaehaNMRT 82

                          90
                  ....*....|....*...
gi 256818761  644 YYLTAESPSLLEEWIRVL 661
Cdd:cd13248    83 YYFAADTAEEMEQWMNAM 100

Rho GTPase activating protein 25 and related proteins Pleckstrin homology (PH) domain; RhoGAP25 (also called ArhGap25) like other RhoGaps are involved in cell polarity, cell morphology and cytoskeletal organization. They act as GTPase activators for the Rac-type GTPases by converting them to an inactive GDP-bound state and control actin remodeling by inactivating Rac downstream of Rho leading to suppress leading edge protrusion and promotes cell retraction to achieve cellular polarity and are able to suppress RAC1 and CDC42 activity in vitro. Overexpression of these proteins induces cell rounding with partial or complete disruption of actin stress fibers and formation of membrane ruffles, lamellipodia, and filopodia. This hierarchy contains RhoGAP22, RhoGAP24, and RhoGAP25. Members here contain an N-terminal PH domain followed by a RhoGAP domain and either a BAR or TATA Binding Protein (TBP) Associated Factor 4 (TAF4) domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 256818761  575 KSGYLLKMGSRVKTWKRRWFVLRQGQILYYKSPSDVirKPQGQVDLNShCQI----VREEEAQ--TFQLI---------S 639
Cdd:cd13263     5 KSGWLKKQGSIVKNWQQRWFVLRGDQLYYYKDEDDT--KPQGTIPLPG-NKVkevpFNPEEPGkfLFEIIpggggdrmtS 81

                          90       100
                  ....*....|....*....|..
gi 256818761  640 GNKTYYLTAESPSLLEEWIRVL 661
Cdd:cd13263    82 NHDSYLLMANSQAEMEEWVKVI 103