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        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 998069410 1237 PTLVPVTHVMMCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYLKDRMAKVCDGCFGELKKR 1303
Cdd:cd15742     1 PTLVPVSHVMMCMNCGSDFTLTLRRHHCHACGKIVCRNCSRNKYPLKYLKDRPAKVCDGCFAELRKR 67

Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 998069410 1356 EDKVALESMPLLGFTIAPEKEEGSSEVGPIFHLYHKKTLFYSFKAEDTNSAQRWIEAM 1413
Cdd:cd13237    34 EDVVALESVPLLGFTVVTIDESFEEDESLVFQLLHKGQLPIIFRADDAETAQRWIEAL 91

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        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 998069410 1237 PTLVPVTHVMMCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYLKDRMAKVCDGCFGELKKR 1303
Cdd:cd15742     1 PTLVPVSHVMMCMNCGSDFTLTLRRHHCHACGKIVCRNCSRNKYPLKYLKDRPAKVCDGCFAELRKR 67

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 998069410    896 IAQELLSSEKAYVEMLQHLNLDFHGAVMRALDDMDHEGRDTLareelrqgLSELPAIHDLHQGILEELEERLSNWE-SQQ 974
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKLLSPNELETL--------FGNIEEIYEFHRDFLDELEERIEEWDdSVE 72

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 998069410    975 KVADVFLAREQGFDHHATHILQFDRYLGLLSEnCLHSPRLAAAVREFEQSVQGGSQTAKHRLLRVVQRLFQYQVLLTDYL 1054
Cdd:smart00325   73 RIGDVFLKLEEFFKIYSEYCSNHPDALELLKK-LKKNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKELL 151

                           170       180
                    ....*....|....*....|....*....
gi 998069410   1055 NNLCPDSAEYDNTQGALSLISKVTDRAND 1083
Cdd:smart00325  152 KHTPEDHEDREDLKKALKAIKELANQVNE 180

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        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*....
gi 998069410   1245 VMMCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYL-KDRMAKVCDGCFGELKK 1302
Cdd:smart00064   10 VSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLgIERPVRVCDDCYENLNG 68

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6 pleckstrin homology (PH) domain, C-terminus; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH 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
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 998069410 1356 EDKVALESMPLLGFTIAPEKEEGSSEVGPIFHLYHKKTLFYSFKAEDTNSAQRWIEAM 1413
Cdd:cd13237    34 EDVVALESVPLLGFTVVTIDESFEEDESLVFQLLHKGQLPIIFRADDAETAQRWIEAL 91

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 998069410  1116 KEGTLMKVTGKNR---RPRHLFLMNDVLL-YTYPQKDGKYRLKNTLAVANMKVSRPV---MEKVPYALKIETSES----C 1184
Cdd:pfam00169    3 KEGWLLKKGGGKKkswKKRYFVLFDGSLLyYKDDKSGKSKEPKGSISLSGCEVVEVVasdSPKRKFCFELRTGERtgkrT 82

                           90       100
                   ....*....|....*....|...
gi 998069410  1185 LMLSASSCAERDEWYGCLSRALP 1207
Cdd:pfam00169   83 YLLQAESEEERKDWIKAIQSAIR 105

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
                    ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 998069410   1356 EDKVALESMPLLGFTIAPEKEEGSSEVGPIFHLYHKKTLFYSFKAEDTNSAQRWIEAMEDAS 1417
Cdd:smart00233   40 KSYKPKGSIDLSGCTVREAPDPDSSKKPHCFEIKTSDRKTLLLQAESEEEREKWVEALRKAI 101

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6, N-terminal Pleckstrin Homology (PH) domain; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH 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 998069410 1101 VRGQGDLLQPGREFLKEGTLMKVTGKNRRPRHLFLMNDVLLYTYPQKD-GKYRLKNTLAVANMKVSRPVMEKVPYALKIE 1179
Cdd:cd13389     1 LLGQYNIVKPGRKLIKEGELMKVSRKEMQPRYFFLFNDCLLYTTPVQSsGMLKLNNELPLSGMKVKLPEDEEYSNEFQII 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 998069410 1180 TSESCLMLSASSCAERDEWYGCLSRALPEDYKAQALAAFHHSVE 1223
Cdd:cd13389    81 STKRSFTLIASSEEERDEWVKALSRAIEEHTKKQRTFAENVSGV 124

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia family proteins, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). 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 998069410 1116 KEGTLMKVTGKN--RRPRHLFLMNDVLLYTYPQKDG---KYRLKNTLAVANMKVSRPVMEKVPYALKIETSESCLMLSAS 1190
Cdd:cd13328     1 KEGQILKLSAKNgtPQPRYLFLFNDMLLYCVPKLSLvgqKFSVRNRLDVAGMKVREPVNENYPHTFKISGKERSLELQAS 80

                          90
                  ....*....|..
gi 998069410 1191 SCAERDEWYGCL 1202
Cdd:cd13328    81 SAEEKDEWIQAI 92

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia protein 6, N-terminal Pleckstrin Homology (PH) domain; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH 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 998069410 1103 GQGDLLQPGREFLKEGTLMKVTGKNRRPRHLFLMNDVLLYTYPQKDGKYRLKNTLAVANMKVSRPVMEKVPYALKIETSE 1182
Cdd:cd15793     3 GHHEIVQPGRVFLKEGTLMKLSRKVMQPRMFFLFNDALLYTTPVQSGMYKLNNMLSLAGMKVSKPSQEAYQNELNIESVE 82

                          90       100
                  ....*....|....*....|....*...
gi 998069410 1183 SCLMLSASSCAERDEWYGCLSRALpEDY 1210
Cdd:cd15793    83 RSFILSASSATERDEWLEAISRAI-EEY 109

FYVE domain found in FYVE, RhoGEF and PH domain-containing protein 6 (FGD6) and similar proteins; FGD6, also termed zinc finger FYVE domain-containing protein 24 is a putative Cdc42-specific guanine nucleotide exchange factor (GEF) whose biological function remains unclear. It is a homologue of FGD1 and contains a DBL homology (DH) domain and pleckstrin homology (PH) domain in the middle region, a FYVE domain, and another PH domain in the C-terminus, but lacks the N-terminal proline-rich domain (PRD) found in FGD1. Moreover, the FYVE domain of FGD6 is a canonical 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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 998069410 1237 PTLVPVTHVMMCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYLKDRMAKVCDGCF 1297
Cdd:cd15743     1 PIWIPDSRVTMCMICTSEFTVTWRRHHCRACGKVVCGSCSSNKAPLEYLKNKSARVCDECF 61

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        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*....
gi 998069410   1245 VMMCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYL-KDRMAKVCDGCFGELKK 1302
Cdd:smart00064   10 VSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLgIERPVRVCDDCYENLNG 68

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6 pleckstrin homology (PH) domain, C-terminus; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH 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
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 998069410 1356 EDKVALESMPLLGFTIAPEKEEGSSEVGPIFHLYHKKTLFYSFKAEDTNSAQRWIEAM 1413
Cdd:cd13237    34 EDVVALESVPLLGFTVVTIDESFEEDESLVFQLLHKGQLPIIFRADDAETAQRWIEAL 91

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        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 998069410 1247 MCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYLKD-RMAKVCDGCF 1297
Cdd:cd00065     1 RCMLCGKKFSLFRRRHHCRRCGRVFCSKCSSKKLPLPSFGSgKPVRVCDSCY 52

FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins Pleckstrin Homology (PH) domain, repeat 1; Members here include FARP1 (also called Chondrocyte-derived ezrin-like protein; PH domain-containing family C member 2), FARP2 (also called FIR/FERM domain including RhoGEF; FGD1-related Cdc42-GEF/FRG), and FARP6 (also called Zinc finger FYVE domain-containing protein 24). They are members of the Dbl family guanine nucleotide exchange factors (GEFs) which are upstream positive regulators of Rho GTPases. Little is known about FARP1 and FARP6, though FARP1 has increased expression in differentiated chondrocytes. FARP2 is thought to regulate neurite remodeling by mediating the signaling pathways from membrane proteins to Rac. It is found in brain, lung, and testis, as well as embryonic hippocampal and cortical neurons. FARP1 and FARP2 are composed of a N-terminal FERM domain, a proline-rich (PR) domain, Dbl-homology (DH), and two C-terminal PH domains. FARP6 is composed of Dbl-homology (DH), and two C-terminal PH domains separated by a FYVE domain. This hierarchy contains the first PH repeat. 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 998069410 1107 LLQPGREFLKEGTLMKVTGKNRRPRHLFLMNDVLLYTY--PQKDGKYRLKNTLAVANMKV--SRPVMEkVPYALKIETSE 1182
Cdd:cd01220     1 LVQPGREFIREGCLQKLSKKGLQQRMFFLFSDVLLYTSrsPTPSLQFKVHGQLPLRGLMVeeSEPEWG-VAHCFTIYGGN 79

                          90       100
                  ....*....|....*....|...
gi 998069410 1183 SCLMLSASSCAERDEWYGCLSRA 1205
Cdd:cd01220    80 RALTVAASSEEEKERWLEDLQRA 102

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 998069410 1247 MCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYLKDRMA--KVCDGCF 1297
Cdd:cd15760     7 RCDVCRKKFGLFKRRHHCRNCGDSFCSEHSSRRIPLPHLGPLGVpqRVCDRCF 59

FYVE domain found in lateral signaling target protein 2 homolog (Lst2) and similar proteins; Lst2, also termed zinc finger FYVE domain-containing protein 28, is a monoubiquitinylated phosphoprotein that functions as a negative regulator of epidermal growth factor receptor (EGFR) signaling. Unlike other FYVE domain-containing proteins, Lst2 displays primarily non-endosomal localization. Its endosomal localization is regulated by monoubiquitinylation. Lst2 physically binds Trim3, also known as BERP or RNF22, which is a coordinator of endosomal trafficking and interacts with Hrs and a complex that biases cargo recycling.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 998069410 1235 RPPTLVPVTHVMMCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPL-KYLKDRMAKVCDGCF 1297
Cdd:cd15731     1 DPPLWVPDEACPQCMACSAPFTVLRRRHHCRNCGKIFCSRCSSNSVPLpRYGQMKPVRVCNHCF 64

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        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 998069410 1247 MCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYLK-DRMAKVCDGCFGEL 1300
Cdd:cd15719    11 SCTGCSVRFSLTERRHHCRNCGQLFCSKCSRFESEIRRLRiSRPVRVCQACYNIL 65

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        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 998069410 1247 MCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYLK-DRMAKVCDGCF 1297
Cdd:cd15735     8 VCMRCRTAFTFTNRKHHCRNCGGVFCQQCSSKSLPLPHFGiNQPVRVCDGCY 59

FYVE domain found in protein containing both PH and FYVE domains 1 (phafin-1) and similar proteins; Phafin-1, also termed lysosome-associated apoptosis-inducing protein containing PH (pleckstrin homology) and FYVE domains (LAPF), or pleckstrin homology domain-containing family F member 1 (PKHF1), or PH domain-containing family F member 1, or apoptosis-inducing protein, or PH and FYVE domain-containing protein 1, or zinc finger FYVE domain-containing protein 15, is a representative of a novel family of PH and FYVE domain-containing proteins called phafins. It is a ubiquitously expressed pro-apoptotic protein via translocating to lysosomes, facilitating apoptosis induction through a lysosomal-mitochondrial apoptotic pathway.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 998069410 1240 VPVTHVMMCMNCG-CDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYLKDRMAKVCDGCFGEL 1300
Cdd:cd15754     3 IPDKATDICMRCTqTNFSLLTRRHHCRKCGFVVCHECSRQRFLIPRLSPKPVRVCSLCYRKL 64

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 998069410 1116 KEGTLMKVTG---KNRRPRHLFLMNDVLLYTYPQKDGKYRLKNTLAVAN-MKVSRPVMEKVPYALKIETSES-CLMLSAS 1190
Cdd:cd00821     1 KEGYLLKRGGgglKSWKKRWFVLFEGVLLYYKSKKDSSYKPKGSIPLSGiLEVEEVSPKERPHCFELVTPDGrTYYLQAD 80

                          90
                  ....*....|..
gi 998069410 1191 SCAERDEWYGCL 1202
Cdd:cd00821    81 SEEERQEWLKAL 92

FYVE domain found in FYVE and coiled-coil domain-containing protein 1 (FYCO1) and similar proteins; FYCO1, also termed zinc finger FYVE domain-containing protein 7, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding protein that is associated with the exterior of autophagosomes and mediates microtubule plus-end-directed vesicle transport. It acts as an effector of GTP-bound Rab7, a GTPase that recruits FYCO1 to autophagosomes and has been implicated in autophagosome-lysosomal fusion. FYCO1 also interacts with two microtubule motor proteins, kinesin (KIF) 5B and KIF23, and thus functions as a platform for assembly of vesicle fusion and trafficking factors. FYCO1 contains an N-terminal alpha-helical RUN domain followed by a long central coiled-coil region, a FYVE domain and a GOLD (Golgi dynamics) domain in C-terminus.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 998069410 1242 VTHvmmCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNkYPLKYLKDRMAKVCDGCF 1297
Cdd:cd15726     7 VTH---CLDCKSEFSWMVRRHHCRLCGRIFCYACSNF-YVLTAHGGKKERCCKACF 58

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 1-4 and similar proteins, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. They play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway. FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. 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 998069410 1115 LKEGTLMKVTGKNRRP--RHLFLMNDVLLYTYPQK---DGKYRLKNTLAVANMKVSRPVMEKVPYALKIETSESCLMLSA 1189
Cdd:cd13388     2 IKEGKILKISARNGDTqeRYLFLFNDMLLYCSPRLrliGQKYKVRARFDVDGMQVLEGDNLETPHTFYVRGKQRSLELQA 81

                  ....*....
gi 998069410 1190 SSCAERDEW 1198
Cdd:cd13388    82 STQEEKAEW 90

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 4, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. 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 998069410 1114 FLKEGTLMKVTGKNR--RPRHLFLMNDVLLYTYPQKD---GKYRLKNTLAVANMKVSRPVMEKVPYALKIETSESCLMLS 1188
Cdd:cd15791     1 LIKEGQILKLAARNTsaQERYLFLFNNMLLYCVPKFSlvgSKYTVRTRIGIDGMKVVETQNEDYPHTFQVSGKERTLELQ 80

                          90
                  ....*....|
gi 998069410 1189 ASSCAERDEW 1198
Cdd:cd15791    81 ASSEQDKEEW 90

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        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 998069410 1240 VPVTHVMMCMNCGCD-FSLTLRRHHCHACGKIVCRNCSRNKYPLKYLKDRMAKVCDGCF 1297
Cdd:cd15724     2 VPDEAVSVCMVCQVErFSMFNRRHHCRRCGRVVCSSCSTKKMLVEGYRENPVRVCDQCY 60

FYVE domain found in FYVE finger-containing Rab5 effector protein rabenosyn-5 (Rbsn-5) and similar proteins; Rbsn-5, also termed zinc finger FYVE domain-containing protein 20, is a novel Rab5 effector that is complexed to the Sec1-like protein VPS45 and recruited in a phosphatidylinositol-3-kinase-dependent fashion to early endosomes. It also binds to Rab4 and EHD1/RME-1, two regulators of the recycling route, and is involved in cargo recycling to the plasma membrane. Moreover, Rbsn-5 regulates endocytosis at the apical side of the wing epithelium and plays a role of the apical endocytic trafficking of Fmi in the establishment of planar cell polarity (PCP).

                          10        20        30
                  ....*....|....*....|....*....|..
gi 998069410 1245 VMMCMNCGCDFSLTLRRHHCHACGKIVCRNCS 1276
Cdd:cd15716    10 VPFCPDCGKKFNLARRRHHCRLCGSIMCNKCS 41

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia protein 3, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. However, FGD1 and FGD3 induced significantly different morphological changes in HeLa Tet-Off cells and while FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTP-bound Cdc42 was significantly increased by the inducible expression of FGD3. They also reciprocally regulated cell motility in inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migration while FGD3 inhibited it. FGD1 and FGD3 therefore play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway through SCF(FWD1/beta-TrCP). 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 998069410 1114 FLKEGTLMKVTGKNRRP--RHLFLMNDVLLYTYPQ---KDGKYRLKNTLAVANMKVSRPVMEKVPYALKIETSESCLMLS 1188
Cdd:cd13387     1 LIKEGHIQKLSAKNGTAqdRYLYLFNSMVLYCVPKlrlMGQKFSVREKIDIAGMQVQEIVKQNVPHTFTITGKKRSLELQ 80

                          90
                  ....*....|
gi 998069410 1189 ASSCAERDEW 1198
Cdd:cd13387    81 ARTEEEKKEW 90

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        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 998069410 1240 VPVTHVMMCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYLK-DRMAKVCDGCF 1297
Cdd:cd15734     3 VPDSEIKECSVCKRPFSPRLSKHHCRACGQGVCDDCSKNRRPVPSRGwDHPVRVCDPCA 61

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        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 998069410 1245 VMMCMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPlKYLKDRMAKVCDGCF 1297
Cdd:cd15739    10 VDQCPNCKTPFSVGKRKHHCRHCGKIFCSDCLTKTVP-SGPNRRPARVCDVCH 61

FYVE domain found in WD40 repeat and FYVE domain-containing protein 1 (WDFY1) and similar proteins; WDFY1, also termed FYVE domain containing protein localized to endosomes-1 (FENS-1), or phosphoinositide-binding protein 1, or zinc finger FYVE domain-containing protein 17, is a novel single FYVE domain containing protein that binds phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) with high specificity over other phosphoinositides. WDFY1 to early endosomes requires an intact FYVE domain and is inhibited by wortmannin, a PI3-kinase inhibitor. In addition to FYVE domain, WDFY1 harbors multiple WD-40 repeats.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 998069410 1256 SLTLRRHHCHACGKIVCRNCS--RNKYPLKYLKDRMaKVCDGCFGELK 1301
Cdd:cd15756    28 TLGLRQHHCRKCGQAVCGKCSskRSSYPIMGFEFQV-RVCDSCFETIK 74

FYVE-like domain found in FYVE, RhoGEF and PH domain-containing protein 3 (FGD3) and similar proteins; FGD3, also termed zinc finger FYVE domain-containing protein 5, is a putative Cdc42-specific guanine nucleotide exchange factor (GEF) that undergoes the ubiquitin ligase SCFFWD1/beta-TrCP-mediated proteasomal degradation. It is a homologue of FGD1 and contains a DBL homology (DH) domain and pleckstrin homology (PH) domain in the middle region, a FYVE domain, and another PH domain in the C-terminus, but lacks the N-terminal proline-rich domain (PRD) found in FGD1. Due to this difference, FGD3 may play different roles from that of FGD1 to regulate cell morphology or motility. The FYVE domain of FGD3 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        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 998069410 1248 CMNCGCDF-SLTLRRHHCHACGKIVCRNCSRnkypLKYLKDRMAKVCDGCF 1297
Cdd:cd15740     8 CKGCNESFnSITKRRHHCKQCGAVICGKCSE----FKDLASRHNRVCRDCF 54

FYVE domain found in RUN and FYVE domain-containing protein 2 (RUFY2) and similar proteins; RUFY2, also termed Rab4-interacting protein related, is a novel embryonic factor that contains an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between. It is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 998069410 1248 CMNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLKYlKDRMAKVCDGCFGELKKR 1303
Cdd:cd15759    13 CKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPS-SPKPVRVCDSCHAMLIQR 67

FYVE-related domain found in uncharacterized myotubularin-related proteins mainly from eumetazoa; This family includes a group of uncharacterized myotubularin-related proteins mainly found in eumetazoa. Although their biological functions remain unclear, they share similar domain architecture that consists of an N-terminal pleckstrin homology (PH) domain, a highly conserved region related to myotubularin proteins, a C-terminal FYVE domain. The model corresponds to the FYVE domain, which resembles the FYVE-related domain as it has an altered sequence in the basic ligand binding patch.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 998069410 1243 THVMMCmNCGCDFSLTLRRHHCHACGKIVCRNCSRNKYPLK-YLKDRMAKVCDGCF 1297
Cdd:cd15738     7 RNVTEC-SCSTPFDHFSKKHHCWRCGNVFCTRCIDKQRALPgHLSQRPVPVCRACY 61