Rabosyn-5 repeating NPF sequence-motif; NPF is a natively unstructured but well-conserved region found in eukaryotic proteins of the Rabenosyn-5 type, wherein the sequence motif arginine-proline-phenylalanine followed by several glutamates and aspartates is repeated up to four times along the sequence. NPF lies between the two Rab-binding domains, for Rab-4 and Rab-5, at the C-terminal end of these proteins. Rabosyn-5 (or rabenosyn) is also involved in cell-polarity determination in developing wing epithelia of Drosophila, when the NPF-motif may be implicated. These NPF motifs create a region of strong positive surface potential which appear to bind Eps15 homology, EH or EF-hand, domains on proteins involved in vesicle trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110  548 SLDFREIGPFQLEPSREPRTHLAYALDLGSSPVPSSTAPKTPSLSSTQ-PTRVWSGPPAVGQERLPQSSMPQQHEGPSLN 626
Cdd:pfam16601   1 SLDFREAKPFQLEPGREPRNHLAHALDLGSSPVRSNTAPKTPSPTSVQePIRLWSGFPALGQEILPQSTESQQNEVASLN 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110  627 PFDEEDLSSPMEEATTGPPAAGVSLDPSARIL---KEYNPFEEEDEEEEAVagnpfiQPDSPAPNPFSEEDEHPQQRLSS 703
Cdd:pfam16601  81 PFEEEELSSPLEEDPTNPFAEDPSPGPSAAVPsdkKEYNPFEEEEEEEANA------DADSPAPNPFEEEDENPFQKPSS 154

                         170       180
                  ....*....|....*....|....
gi 697960110  704 PLVPGNPFEEPTCINPFEMDSDSG 727
Cdd:pfam16601 155 PPVPGNPFEEPTSTNPFEVDSDSE 178

Rabenosyn Rab binding domain; Rabenosyn-5 (Rbsn) is a multivalent effector with interacts with the Rab family.Rsbn contains distinct Rab4 and Rab5 binding sites within residues 264-500 and 627-784 respectively. Rab proteins are GTPases involved in the regulation of all stages of membrane trafficking.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 697960110  461 QQIHNITSFIRQAKAAGRMDEVRTLQENLRQLQDEYDQQ 499
Cdd:pfam11464   1 EQIFLVESMIKQAKKARRFDEVATLEENLRELQREIDRL 39

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110  398 AVERQAALESQRR-LEERQSGLASR--AANGEVASLRRgpaplrKAEGWLPLSGGQGQSEDSDPLLQQIHNITSFIRQAK 474
Cdd:COG4913   608 NRAKLAALEAELAeLEEELAEAEERleALEAELDALQE------RREALQRLAEYSWDEIDVASAEREIAELEAELERLD 681

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 697960110  475 AAgrMDEVRTLQENLRQLQDEYDQQQTEKAiELSRRQAEEEDlQREQLQ 523
Cdd:COG4913   682 AS--SDDLAALEEQLEELEAELEELEEELD-ELKGEIGRLEK-ELEQAE 726

Rabosyn-5 repeating NPF sequence-motif; NPF is a natively unstructured but well-conserved region found in eukaryotic proteins of the Rabenosyn-5 type, wherein the sequence motif arginine-proline-phenylalanine followed by several glutamates and aspartates is repeated up to four times along the sequence. NPF lies between the two Rab-binding domains, for Rab-4 and Rab-5, at the C-terminal end of these proteins. Rabosyn-5 (or rabenosyn) is also involved in cell-polarity determination in developing wing epithelia of Drosophila, when the NPF-motif may be implicated. These NPF motifs create a region of strong positive surface potential which appear to bind Eps15 homology, EH or EF-hand, domains on proteins involved in vesicle trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110  548 SLDFREIGPFQLEPSREPRTHLAYALDLGSSPVPSSTAPKTPSLSSTQ-PTRVWSGPPAVGQERLPQSSMPQQHEGPSLN 626
Cdd:pfam16601   1 SLDFREAKPFQLEPGREPRNHLAHALDLGSSPVRSNTAPKTPSPTSVQePIRLWSGFPALGQEILPQSTESQQNEVASLN 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110  627 PFDEEDLSSPMEEATTGPPAAGVSLDPSARIL---KEYNPFEEEDEEEEAVagnpfiQPDSPAPNPFSEEDEHPQQRLSS 703
Cdd:pfam16601  81 PFEEEELSSPLEEDPTNPFAEDPSPGPSAAVPsdkKEYNPFEEEEEEEANA------DADSPAPNPFEEEDENPFQKPSS 154

                         170       180
                  ....*....|....*....|....
gi 697960110  704 PLVPGNPFEEPTCINPFEMDSDSG 727
Cdd:pfam16601 155 PPVPGNPFEEPTSTNPFEVDSDSE 178

FYVE zinc finger; The FYVE zinc finger is named after four proteins that it has been found in: Fab1, YOTB/ZK632.12, Vac1, and EEA1. The FYVE finger has been shown to bind two Zn++ ions. The FYVE finger has eight potential zinc coordinating cysteine positions. Many members of this family also include two histidines in a motif R+HHC+XCG, where + represents a charged residue and X any residue. We have included members which do not conserve these histidine residues but are clearly related.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 697960110  152 VPWVNDQDVPFCPDCGNKFSIRNRRHHCRLCGSIMCKKCMELISLPL 198
Cdd:pfam01363   1 PVWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISLL 47

Rabenosyn Rab binding domain; Rabenosyn-5 (Rbsn) is a multivalent effector with interacts with the Rab family.Rsbn contains distinct Rab4 and Rab5 binding sites within residues 264-500 and 627-784 respectively. Rab proteins are GTPases involved in the regulation of all stages of membrane trafficking.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 697960110  461 QQIHNITSFIRQAKAAGRMDEVRTLQENLRQLQDEYDQQ 499
Cdd:pfam11464   1 EQIFLVESMIKQAKKARRFDEVATLEENLRELQREIDRL 39

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110  398 AVERQAALESQRR-LEERQSGLASR--AANGEVASLRRgpaplrKAEGWLPLSGGQGQSEDSDPLLQQIHNITSFIRQAK 474
Cdd:COG4913   608 NRAKLAALEAELAeLEEELAEAEERleALEAELDALQE------RREALQRLAEYSWDEIDVASAEREIAELEAELERLD 681

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 697960110  475 AAgrMDEVRTLQENLRQLQDEYDQQQTEKAiELSRRQAEEEDlQREQLQ 523
Cdd:COG4913   682 AS--SDDLAALEEQLEELEAELEELEEELD-ELKGEIGRLEK-ELEQAE 726

Rabosyn-5 repeating NPF sequence-motif; NPF is a natively unstructured but well-conserved region found in eukaryotic proteins of the Rabenosyn-5 type, wherein the sequence motif arginine-proline-phenylalanine followed by several glutamates and aspartates is repeated up to four times along the sequence. NPF lies between the two Rab-binding domains, for Rab-4 and Rab-5, at the C-terminal end of these proteins. Rabosyn-5 (or rabenosyn) is also involved in cell-polarity determination in developing wing epithelia of Drosophila, when the NPF-motif may be implicated. These NPF motifs create a region of strong positive surface potential which appear to bind Eps15 homology, EH or EF-hand, domains on proteins involved in vesicle trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110  548 SLDFREIGPFQLEPSREPRTHLAYALDLGSSPVPSSTAPKTPSLSSTQ-PTRVWSGPPAVGQERLPQSSMPQQHEGPSLN 626
Cdd:pfam16601   1 SLDFREAKPFQLEPGREPRNHLAHALDLGSSPVRSNTAPKTPSPTSVQePIRLWSGFPALGQEILPQSTESQQNEVASLN 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110  627 PFDEEDLSSPMEEATTGPPAAGVSLDPSARIL---KEYNPFEEEDEEEEAVagnpfiQPDSPAPNPFSEEDEHPQQRLSS 703
Cdd:pfam16601  81 PFEEEELSSPLEEDPTNPFAEDPSPGPSAAVPsdkKEYNPFEEEEEEEANA------DADSPAPNPFEEEDENPFQKPSS 154

                         170       180
                  ....*....|....*....|....
gi 697960110  704 PLVPGNPFEEPTCINPFEMDSDSG 727
Cdd:pfam16601 155 PPVPGNPFEEPTSTNPFEVDSDSE 178

FYVE domain 2 found in yeast protein VAC1 (Vac1p) and similar proteins; Vac1p, also termed vacuolar segregation protein Pep7p, or carboxypeptidase Y-deficient protein 7, or vacuolar protein sorting-associated protein 19 (Vps19p), or vacuolar protein-targeting protein 19, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding protein that interacts with a Rab GTPase, GTP-bound form of Vps21p, and a Sec1p homologue, Vps45p, to facilitate Vps45p-dependent vesicle-mediated vacuolar protein sorting. It also acts as a novel regulator of vesicle docking and/or fusion at the endosome and functions in vesicle-mediated transport of Golgi precursor carboxypeptidase Y (CPY), protease A (PrA), protease B (PrB), but not alkaline phosphatase (ALP) from the trans-Golgi network-like compartment (TGN) to the endosome. Vac1p contains an N-terminal classical TFIIIA-like zinc finger, two putative zinc-binding FYVE fingers, and a C-terminal coiled coil region. The family corresponds to the second FYVE domain that is responsible for the ability of Pep7p to efficiently interact with Vac1p and Vps45p.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110 153 PWVNDQDVPFCPDCGNKFSIRNRRHHCRLCGSIMC----KKCMELISLPLankLTSASKESLSTHTSPSQSPnsvhgsrr 228
Cdd:cd15737    1 PWEDDSSVTHCPICLRSFGLLLRKHHCRLCGKVVCddrrTKCSTEVPLDL---LSSALPDLPFVFKEPQSDI-------- 69

                         90       100
                 ....*....|....*....|....*...
gi 697960110 229 gsissmssvssvldEKDDDRIRCCTHCK 256
Cdd:cd15737   70 --------------PDDTKSVRVCRDCK 83

Protein present in Fab1, YOTB, Vac1, and EEA1; The FYVE zinc finger is named after four proteins where it was first found: Fab1, YOTB/ZK632.12, Vac1, and EEA1. The FYVE finger has been shown to bind two Zn2+ ions. The FYVE finger has eight potential zinc coordinating cysteine positions. The FYVE finger is structurally related to the PHD finger and the RING finger. Many members of this family also include two histidines in a motif R+HHC+XCG, where + represents a charged residue and X any residue. The FYVE finger functions in the membrane recruitment of cytosolic proteins by binding to phosphatidylinositol 3-phosphate (PI3P), which is prominent on endosomes. The R+HHC+XCG motif is critical for PI3P binding.

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 697960110   153 PWVNDQDVPFCPDCGNKFSIRNRRHHCRLCGSIMCKKC 190
Cdd:smart00064   3 HWIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKC 40

FYVE domain found in metazoan PIKfyve, fungal and plant Fab1, and similar proteins; PIKfyve, also termed FYVE finger-containing phosphoinositide kinase, or 1-phosphatidylinositol 3-phosphate 5-kinase, or phosphatidylinositol 3-phosphate 5-kinase (PIP5K3), or phosphatidylinositol 3-phosphate 5-kinase type III (PIPkin-III or type III PIP kinase), is a phosphoinositide 5-kinase that forms a complex with its regulators, the scaffolding protein Vac14 and the lipid phosphatase Fig4. The complex is responsible for synthesizing phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2] from phosphatidylinositol 3-phosphate (PtdIns3P or PI3P). Then phosphatidylinositol-5-phosphate (PtdIns5P) is generated directly from PtdIns(3,5)P2. PtdIns(3,5)P2 and PtdIns5P regulate endosomal trafficking and responses to extracellular stimuli. At this point, PIKfyve is vital in early embryonic development. Moreover, PIKfyve forms a complex with ArPIKfyve (associated regulator of PIKfyve) and SAC3 at the endomembranes, which plays a role in receptor tyrosine kinase (RTK) degradation. The phosphorylation of PIKfyve by AKT can facilitate Epidermal growth factor receptor (EGFR) degradation. In addition, PIKfyve may participate in the regulation of the glutamate transporters EAAT2, EAAT3 and EAAT4, and the cystic fibrosis transmembrane conductance regulator (CFTR). It is also essential for systemic glucose homeostasis and insulin-regulated glucose uptake/GLUT4 translocation in skeletal muscle. It can be activated by protein kinase B (PKB/Akt) and further up-regulates human ether-a-go-go (hERG) channels. This family also includes the yeast and plant orthologs of human PIKfyve, Fab1. PIKfyve and its orthologs share a similar architecture. They contain an N-terminal FYVE domain, a middle region related to the CCT/TCP-1/Cpn60 chaperonins that are involved in productive folding of actin and tubulin, a second middle domain that contains a number of conserved cysteine residues (CCR) unique to this family, and a C-terminal lipid kinase domain related to PtdInsP kinases.

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 697960110 154 WVNDQDVPFCPDCGNKFSIRNRRHHCRLCGSIMCKKC 190
Cdd:cd15725    2 WMPDSSCKECYECSEKFTTFRRRHHCRLCGQIFCSRC 38

FYVE domain like superfamily; FYVE domain is a 60-80 residue double zinc finger motif-containing module named after the four proteins, Fab1, YOTB, Vac1, and EEA1. The canonical FYVE domains are distinguished from other zinc fingers by three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif, which form a compact phosphatidylinositol 3-phosphate (PtdIns3P, also termed PI3P)-binding site. They are found in many membrane trafficking regulators, including EEA1, Hrs, Vac1p, Vps27p, and FENS-1, which locate to early endosomes, specifically bind PtdIns3P, and play important roles in vesicular traffic and in signal transduction. Some proteins, such as rabphilin-3A and alpha-Rab3-interacting molecules (RIMs), are also involved in membrane trafficking and bind to members of the Rab subfamily of GTP hydrolases. However, they contain FYVE-related domains that are structurally similar to the canonical FYVE domains but lack the three signature sequences. At this point, they may not bind to phosphoinositides. In addition, this superfamily also contains the third group of proteins, caspase-associated ring proteins CARP1 and CARP2. They do not localize to membranes in the cell and are involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8 and caspase 10, which are distinguished from other FYVE-type proteins. Moreover, these proteins have an altered sequence in the basic ligand binding patch and lack the WxxD motif that is conserved only in phosphoinositide binding FYVE domains. Thus they constitute a family of unique FYVE-type domains called FYVE-like domains. The FYVE domain is structurally similar to the RING domain and the PHD finger. This superfamily also includes ADDz zinc finger domain, which is a PHD-like zinc finger motif that contains two parts, a C2-C2 and a PHD-like zinc finger.

                         10        20
                 ....*....|....*....|....*....
gi 697960110 163 CPDCGNKFSIRNRRHHCRLCGSIMCKKCM 191
Cdd:cd00065    2 CMLCGKKFSLFRRRHHCRRCGRVFCSKCS 30

FYVE domain found in endofin and similar proteins; Endofin, also termed zinc finger FYVE domain-containing protein 16 (ZFY16), or endosome-associated FYVE domain protein, is a FYVE domain-containing protein that is localized to EEA1-containing endosomes. It is regulated by phosphoinositol lipid and engaged in endosome-mediated receptor modulation. Endofin is involved in Bone morphogenetic protein (BMP) signaling through interacting with Smad1 preferentially and enhancing Smad1 phosphorylation and nuclear localization upon BMP stimulation. It also functions as a scaffold protein that brings Smad4 to the proximity of the receptor complex in Transforming growth factor (TGF)-beta signaling. Moreover, endofin is a novel tyrosine phosphorylation target downstream of epidermal growth factor receptor (EGFR) in EGF-signaling. In addition, endofin plays a role in endosomal trafficking by recruiting cytosolic TOM1, an important molecule for membrane recruitment of clathrin, onto endosomal membranes.

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 697960110 154 WVNDQDVPFCPDCGNKFSIRNRRHHCRLCGSIMCKKC 190
Cdd:cd15729    7 WVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSAC 43

FYVE domain found in WD40 repeat and FYVE domain-containing protein 3 (WDFY3) and similar proteins; WDFY3, also termed autophagy-linked FYVE protein (Alfy), is a ubiquitously expressed phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein required for selective macroautophagic degradation of aggregated proteins. It regulates the protein degradation through the direct interaction with the autophagy protein Atg5. Moreover, WDFY3 acts as a scaffold that bridges its cargo to the macroautophagic machinery via the creation of a greater complex with Atg12, Atg16L, and LC3. It also functionally associates with sequestosome-1/p62 (SQSTM1) in osteoclasts. WDFY3 shuttles between the nucleus and cytoplasm. It predominantly localizes to the nucleus and nuclear membrane under basal conditions, but is recruited to cytoplasmic ubiquitin-positive protein aggregates under stress conditions. WDFY3 contains a PH-BEACH domain assemblage, five WD40 repeats and a PtdIns3P-binding FYVE domain.

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 697960110 154 WVNDQDVPFCPDCGNKFSIRNRRHHCRLCGSIMCKKC 190
Cdd:cd15719    3 WVKDEGGDSCTGCSVRFSLTERRHHCRNCGQLFCSKC 39

FYVE domain found in myotubularin-related protein 4 (MTMR4) and similar proteins; MTMR4, also termed FYVE domain-containing dual specificity protein phosphatase 2 (FYVE-DSP2), or zinc finger FYVE domain-containing protein 11, is an dual specificity protein phosphatase that specifically dephosphorylates phosphatidylinositol 3-phosphate (PtdIns3P or PI3P). It is localizes to early endosomes, as well as to Rab11- and Sec15-positive recycling endosomes, and regulates sorting from early endosomes. Moreover, MTMR4 is preferentially associated with and dephosphorylated the activated regulatory Smad proteins (R-Smads) in cytoplasm to keep transforming growth factor (TGF) beta signaling in homeostasis. It also functions as an essential negative modulator for the homeostasis of bone morphogenetic protein (BMP)/decapentaplegic (Dpp) signaling. In addition, MTMR4 acts as a novel interactor of the ubiquitin ligase Nedd4 (neural-precursor-cell-expressed developmentally down-regulated 4) and may play a role in the biological process of muscle breakdown. MTMR4 contains an N-terminal PH-GRAM (PH-G) domain, a MTM phosphatase domain, a coiled-coil region, and a C-terminal FYVE domain.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 697960110 154 WVNDQDVPFCPDCGNKFSIRNRRHHCRLCGSIMCKKCMELiSLPLANK 201
Cdd:cd15733    1 WVPDHAASHCFGCDCEFWLAKRKHHCRNCGNVFCADCSNY-KLPIPDE 47

FYVE domain found in RUN and FYVE domain-containing protein RUFY1, RUFY2 and similar proteins; This family includes RUN and FYVE domain-containing protein RUFY1 and RUFY2. RUFY1, also termed FYVE-finger protein EIP1, or La-binding protein 1, or Rab4-interacting protein (Rabip4), or Zinc finger FYVE domain-containing protein 12 (ZFY12), a human homologue of mouse Rabip4, an effector of Rab4 GTPase that regulates recycling of endocytosed cargo. RUFY1 is an endosomal protein that functions as a dual effector of Rab4 and Rab14 and is involved in efficient recycling of transferrin (Tfn). It is a downstream effector of Etk, a downstream tyrosine kinase of PI3-kinase that is involved in regulation of vesicle trafficking. RUFY2, also termed Rab4-interacting protein related, is a novel embryonic factor that is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions. Both RUFY1 and RUFY2 contain an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 697960110 154 WVNDQDVPFCPDCGNKFSIRNRRHHCRLCGSIMCKKCMElISLPLAN 200
Cdd:cd15721    1 WADDKEVTHCQQCEKEFSLSRRKHHCRNCGGIFCNSCSD-NTMPLPS 46

FYVE domain found in uncharacterized rab GTPase-binding effector proteins from bilateria; This family includes a group of uncharacterized rab GTPase-binding effector proteins found in bilateria. Although their biological functions remain unclear, they all contain a FYVE domain that harbors a putative phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding site.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|
gi 697960110 152 VPWVNDQDVPFCPDCGNKFSIRNRRHHCRLCGSIMCKKCM 191
Cdd:cd15739    2 VRWQHEDDVDQCPNCKTPFSVGKRKHHCRHCGKIFCSDCL 41

FYVE domain found in Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and similar proteins; scVps27p, also termed Golgi retention defective protein 11, is the putative yeast counterpart of the mammalian protein Hrs and is involved in endosome maturation. It is a mono-ubiquitin-binding protein that interacts with ubiquitinated cargoes, such as Hse1p, and is required for protein sorting into the multivesicular body. Vps27p forms a complex with Hse1p. The complex binds ubiquitin and mediates endosomal protein sorting. At the endosome, Vps27p and a trimeric protein complex, ESCRT-1, bind ubiquitin and are important for multivesicular body (MVB) sorting. Vps27p contains an N-terminal VHS (Vps27/Hrs/STAM) domain, a FYVE domain that binds PtdIns3P, followed by two ubiquitin-interacting motifs (UIMs), and a C-terminal clathrin-binding motif.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 697960110 153 PWVNDqdvPFCPDCGNKFSIRNRRHHCRLCGSIMCKK-CMELISLPLANKLTSASK 207
Cdd:cd15760    1 HWKPD---SRCDVCRKKFGLFKRRHHCRNCGDSFCSEhSSRRIPLPHLGPLGVPQR 53

FYVE domain found in FYVE, RhoGEF and PH domain-containing protein facio-genital dysplasia FGD1, FGD2, FGD4; This family represents a group of Rho GTPase cell division cycle 42 (Cdc42)-specific guanine nucleotide exchange factors (GEFs), including FYVE, RhoGEF and PH domain-containing protein FGD1, FGD2 and FGD4. FGD1, also termed faciogenital dysplasia 1 protein, or Rho/Rac guanine nucleotide exchange factor FGD1 (Rho/Rac GEF), or zinc finger FYVE domain-containing protein 3, is a central regulator of extracellular matrix remodeling and belongs to the DBL family of GEFs that regulate the activation of the Rho GTPases. FGD1 is encoded by gene FGD1. Disabling mutations in the FGD1 gene cause the human X-linked developmental disorder faciogenital dysplasia (FGDY, also known as Aarskog-Scott syndrome). FGD2, also termed zinc finger FYVE domain-containing protein 4, is expressed in antigen-presenting cells, including B lymphocytes, macrophages, and dendritic cells. It localizes to early endosomes and active membrane ruffles. It plays a role in leukocyte signaling and vesicle trafficking in cells specialized to present antigen in the immune system. FGD4, also termed actin filament-binding protein frabin, or FGD1-related F-actin-binding protein, or zinc finger FYVE domain-containing protein 6, functions as an F-actin-binding (FAB) protein showing significant homology to FGD1. It induces the formation of filopodia through the activation of Cdc42 in fibroblasts. Those FGD proteins possess a similar domain organization that contains a DBL homology (DH) domain, a pleckstrin homology (PH) domain, a FYVE domain, and another PH domain in the C-terminus. However, each FGD has a unique N-terminal region that may directly or indirectly interact with F-actin. FGD1 and FGD4 have an N-terminal proline-rich domain (PRD) and an N-terminal F-actin binding (FAB) domain, respectively. This model corresponds to the FYVE domain, which has been found in many proteins involved in membrane trafficking and phosphoinositide metabolism, and has been defined by three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCR patch, and a C-terminal RVC motif, which form a compact phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding site. FGD1 possesses a FYVE-like domain that lack the N-terminal WxxD motif. Moreover, FGD2 is the only known RhoGEF family member shown to have a functional FYVE domain and endosomal binding activity.

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 697960110 154 WVNDQDVPFCPDCGNKF-SIRNRRHHCRLCGSIMCKKC 190
Cdd:cd15741    3 WVRDNEVTMCMRCKEPFnALTRRRHHCRACGYVVCWKC 40

FYVE domain found in FYVE domain-containing protein 26 (ZFY26 or ZFYVE26); ZFY26, also termed FYVE domain-containing centrosomal protein (FYVE-CENT), or spastizin, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein that localizes to the centrosome and midbody. ZFY26 and its interacting partners TTC19 and KIF13A are required for cytokinesis. It also interacts with Beclin 1, a subunit of class III phosphatidylinositol 3-kinase complex, and may have potential implications for carcinogenesis. In addition, it has been considered as the causal agent of a rare form of hereditary spastic paraplegia. ZFY26 contains a FYVE domain that is important for targeting of FYVE-CENT to the midbody.

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 697960110 154 WVNDQDVPFCPDCGN-KFSIRNRRHHCRLCGSIMCKKC 190
Cdd:cd15724    1 WVPDEAVSVCMVCQVeRFSMFNRRHHCRRCGRVVCSSC 38

FYVE domain found in protein containing both PH and FYVE domains 2 (phafin-2) and similar proteins; Phafin-2, also termed endoplasmic reticulum-associated apoptosis-involved protein containing PH and FYVE domains (EAPF), or pleckstrin homology domain-containing family F member 2 (PKHF2), or PH domain-containing family F member 2, or PH and FYVE domain-containing protein 2, or zinc finger FYVE domain-containing protein 18, is a ubiquitously expressed endoplasmic reticulum-associated protein that facilitates tumor necrosis factor alpha (TNF-alpha)-triggered cellular apoptosis through endoplasmic reticulum (ER)-mitochondrial apoptotic pathway. It is an endosomal phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) effector, as well as an interactor of the endosomal-tethering protein EEA1. It regulates endosome fusion upstream of Rab5. Phafin-2 also functions as a novel regulator of endocytic epidermal growth factor receptor (EGFR) degradation through a role in endosomal fusion.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|
gi 697960110 154 WVNDQDVPFCPDCGN-KFSIRNRRHHCRLCGSIMCKKCME 192
Cdd:cd15755    2 WVPDSEATVCMRCQKaKFTPVNRRHHCRKCGFVVCGPCSE 41

FYVE domain found in Schizosaccharomyces pombe vacuolar protein sorting-associated protein 27 (spVps27p) and similar proteins; spVps27p, also termed suppressor of ste12 deletion protein 4 (Sst4p), is a conserved homolog of budding Saccharomyces cerevisiae Vps27 and of mammalian Hrs. It functions as a downstream factor for phosphatidylinositol 3-kinase (PtdIns 3-kinase) in forespore membrane formation with normal morphology. It colocalizes and interacts with Hse1p, a homolog of Saccharomyces cerevisiae Hse1p and of mammalian STAM, to form a complex whose ubiquitin-interacting motifs (UIMs) are important for sporulation. spVps27p contains a VHS (Vps27p/Hrs/Stam) domain, a FYVE domain, and two UIMs.

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 697960110 154 WVnDQDVpfCPDCGNKFSIRNRRHHCRLCGSIMCKKC 190
Cdd:cd15735    3 WV-DSDV--CMRCRTAFTFTNRKHHCRNCGGVFCQQC 36

FYVE domains found in zinc finger FYVE domain-containing protein 1 (ZFYV1) and similar proteins; ZFYV1, also termed double FYVE-containing protein 1 (DFCP1), or SR3, or tandem FYVE fingers-1, is a novel tandem FYVE domain containing protein that binds phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) with high specificity over other phosphoinositides. The subcellular distribution of exogenously-expressed ZFYV1 to Golgi, endoplasmic reticulum (ER) and vesicular is governed in part by its FYVE domains but unaffected by wortmannin, a PI3-kinase inhibitor. In addition to C-terminal tandem FYVE domain, ZFYV1 contains an N-terminal putative C2H2 type zinc finger and a possible nucleotide binding P-loop.

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 697960110 154 WVNDQDVPFCPDCGNKFSIRNRRHHCRLCGSIMCKKC 190
Cdd:cd15734    2 WVPDSEIKECSVCKRPFSPRLSKHHCRACGQGVCDDC 38

FYVE domain found in hepatocyte growth factor (HGF)-regulated tyrosine kinase substrate (Hrs) and similar proteins; Hrs, also termed protein pp110, is a tyrosine phosphorylated protein that plays an important role in the signaling pathway of HGF. It is localized to early endosomes and an essential component of the endosomal sorting and trafficking machinery. Hrs interacts with hypertonia-associated protein Trak1, a novel regulator of endosome-to-lysosome trafficking. It can also forms an Hrs/actinin-4/BERP/myosin V protein complex that is required for efficient transferrin receptor (TfR) recycling but not for epidermal growth factor receptor (EGFR) degradation. Moreover, Hrs, together with STAM proteins, STAM1 and STAM2, and EPs15, forms a multivalent ubiquitin-binding complex that sorts ubiquitinated proteins into the multivesicular body pathway, and plays a regulatory role in endocytosis/exocytosis. Furthermore, Hrs functions as an interactor of the neurofibromatosis 2 tumor suppressor protein schwannomin/merlin. It is also involved in the inhibition of citron kinase-mediated HIV-1 budding. Hrs contains a single ubiquitin-interacting motif (UIM) that is crucial for its function in receptor sorting, and a FYVE domain that harbors double Zn2+ binding sites.

                         10        20        30
                 ....*....|....*....|....*....|..
gi 697960110 159 DVPFCPDCGNKFSIRNRRHHCRLCGSIMCKKC 190
Cdd:cd15720    4 DGDECHRCRVQFGVFQRKHHCRACGQVFCGKC 35

FYVE-like domain found in FYVE, RhoGEF and PH domain-containing protein 5 (FGD5) and similar proteins; FGD5, also termed zinc finger FYVE domain-containing protein 23, is an endothelial cell (EC)-specific guanine nucleotide exchange factor (GEF) that regulates endothelial adhesion, survival, and angiogenesis by modulating phosphatidylinositol 3-kinase signaling. It functions as a novel genetic regulator of vascular pruning by activation of endothelial cell-targeted apoptosis. FGD5 is a homologue of FGD1 and contains a DBL homology (DH) domain, a pleckstrin homology (PH) domain, a FYVE domain, and another PH domain in the C-terminus, but lacks the N-terminal proline-rich domain (PRD) found in FGD1. The FYVE domain of FGD5 resembles a FYVE-like domain that is different from the canonical FYVE domains, since it lacks one of the three conserved signature motifs (the WxxD motif) that are involved in phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding and exhibits altered lipid binding specificities.

                         10        20        30
                 ....*....|....*....|....*....|.
gi 697960110 160 VPFCPDCGNKFSIRNRRHHCRLCGSIMCKKC 190
Cdd:cd15742    9 VMMCMNCGSDFTLTLRRHHCHACGKIVCRNC 39

FYVE-related domain found in RUN and FYVE domain-containing protein 4 (RUFY4) and similar proteins; RUFY4 belongs to the FUFY protein family which is characterized by the presence of an N-terminal RUN domain and a C-terminal FYVE domain. The FYVE domain of RUFY4 resembles the FYVE-related domain as it lacks the WxxD motif (x for any residue). The biological function of RUFY4 still remains unclear.

                         10        20
                 ....*....|....*....|....*....
gi 697960110 162 FCPDCGNKFSIRNRRHHCRLCGSIMCKKC 190
Cdd:cd15745    1 ACAICAKAFSLFRRKYVCRLCGGVVCHSC 29

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110  398 AVERQAALESQRR-LEERQSGLASR--AANGEVASLRRgpaplrKAEGWLPLSGGQGQSEDSDPLLQQIHNITSFIRQAK 474
Cdd:COG4913   608 NRAKLAALEAELAeLEEELAEAEERleALEAELDALQE------RREALQRLAEYSWDEIDVASAEREIAELEAELERLD 681

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 697960110  475 AAgrMDEVRTLQENLRQLQDEYDQQQTEKAiELSRRQAEEEDlQREQLQ 523
Cdd:COG4913   682 AS--SDDLAALEEQLEELEAELEELEEELD-ELKGEIGRLEK-ELEQAE 726

FYVE-related domain found in protrudin and similar proteins; Protrudin, also termed zinc finger FYVE domain-containing protein 27 (ZFY27 or ZFYVE27), is a FYVE domain-containing protein involved in transport of neuronal cargoes and implicated in the onset of hereditary spastic paraplegia (HSP). It is involved in neurite outgrowth through binding to spastin. Moreover, it functions as a key regulator of the Rab11-dependent membrane trafficking during neurite extension. It serves as an adaptor molecule that links its associated proteins, such as Rab11-GDP, VAP-A and -B, Surf4, and RTN3, to KIF5, a motor protein that mediates anterograde vesicular transport in neurons, and thus plays a key role in the maintenance of neuronal function. The FYVE domain of protrudin resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif. In addition, unlike canonical FYVE domains that is located to early endosomes and specifically binds to phosphatidylinositol 3-phosphate (PtdIns3P or PI3P), the FYVE domain of protrudin is located to plasma membrane and preferentially binds phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2), and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). In addition to FYVE-related domain, protrudin also contains a Rab11-binding domain (RBD11), two hydrophobic domains, HP-1 and HP-2, an FFAT motif, and a coiled-coil domain.

                         10        20
                 ....*....|....*....|....*....
gi 697960110 163 CPDCGNKFS-IRNRRHHCRLCGSIMCKKC 190
Cdd:cd15723    2 CTGCGASFSvLLKKRRSCNNCGNAFCSRC 30

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110  577 SSPVPSSTAPKTPSlsstQPTRVWSGPPAVGQERLPQSSMPQQheGPSLNPFDEEDLSSPMEEATTGPPAAGVSLD--PS 654
Cdd:pfam03154 195 ATAGPTPSAPSVPP----QGSPATSQPPNQTQSTAAPHTLIQQ--TPTLHPQRLPSPHPPLQPMTQPPPPSQVSPQplPQ 268

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 697960110  655 ARILKEYNPFEEEDEE-----EEAVAGNPFIQPDSPA-----PNPFSEEDEHPQQRL------SSPLVPGNPFEEPTCIN 718
Cdd:pfam03154 269 PSLHGQMPPMPHSLQTgpshmQHPVPPQPFPLTPQSSqsqvpPGPSPAAPGQSQQRIhtppsqSQLQSQQPPREQPLPPA 348

                  ....
gi 697960110  719 PFEM 722
Cdd:pfam03154 349 PLSM 352