Plant-like Phospholipase C (PLC) pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) was the second class of PLC discovered. PLC-gamma consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves internal to which is a PH domain split by two SH2 domains and a single SH3 domain, and a C-terminal C2 domain. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). This cd contains PLC members from fungi and plants. 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 1063722395   12 RDIDQALVSLKKGTQLLKYSRKGRPKFRSFRLSPDETTLFWLS--HGEEKGLKLATVSRILPGQRTAVFRRYLRPEKDYL 89
Cdd:cd13365      1 RDVIEAITQLKIGSYLLKYGRRGKPHFRYFWLSPDELTLYWSSpkKGSEKRVRLSSVSRIIPGQRTVVFKRPPPPGLEEH 80

                           90       100       110
                   ....*....|....*....|....*....|....
gi 1063722395   90 SFSLIYHNGDRSLDLICKDKAETEVWFAGLKSLI 123
Cdd:cd13365     81 SFSIIYADGERSLDLTCKDRQEFDTWFTGLRYLL 114

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        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1063722395   606 HKWVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAALAPTpgKPHRVCDACYTKLK 673
Cdd:smart00064    2 PHWIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLGIE--RPVRVCDDCYENLN 67

Plant-like Phospholipase C (PLC) pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) was the second class of PLC discovered. PLC-gamma consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves internal to which is a PH domain split by two SH2 domains and a single SH3 domain, and a C-terminal C2 domain. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). This cd contains PLC members from fungi and plants. 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 1063722395   12 RDIDQALVSLKKGTQLLKYSRKGRPKFRSFRLSPDETTLFWLS--HGEEKGLKLATVSRILPGQRTAVFRRYLRPEKDYL 89
Cdd:cd13365      1 RDVIEAITQLKIGSYLLKYGRRGKPHFRYFWLSPDELTLYWSSpkKGSEKRVRLSSVSRIIPGQRTVVFKRPPPPGLEEH 80

                           90       100       110
                   ....*....|....*....|....*....|....
gi 1063722395   90 SFSLIYHNGDRSLDLICKDKAETEVWFAGLKSLI 123
Cdd:cd13365     81 SFSIIYADGERSLDLTCKDRQEFDTWFTGLRYLL 114

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        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1063722395   606 HKWVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAALAPTpgKPHRVCDACYTKLK 673
Cdd:smart00064    2 PHWIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLGIE--RPVRVCDDCYENLN 67

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 1063722395  617 CSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAALAptPGKPHRVCDACY 669
Cdd:cd00065      2 CMLCGKKFSLFRRRHHCRRCGRVFCSKCSSKKLPLPSFG--SGKPVRVCDSCY 52

Pleckstrin homology domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1063722395   16 QALVSLKKGTQLLKYSRKGRP-KFRSFRLSPDETTLFW------------LSHGEEKgLKLATVSRILPGQRTAVFRR-- 80
Cdd:pfam16457    4 QRLNCLLEGAWFPKVRGRRRKkKYRFCRLSPNRKVLHYgdfeekptvdpsLESLPEK-IDLSDIKEVVTGKECPHVREsg 82

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 1063722395   81 -YLRPEKDYLSFSLIY-HNGDRSLDLICKDKAETEVWFAGLKSLI 123
Cdd:pfam16457   83 kKSKKTSSTLAFSLIYgADEYELLDFVAPSESVAAIWLDGLNMLL 127

Alpha-tubulin suppressor ATS1 and related RCC1 domain-containing proteins [Cell cycle control, cell division, chromosome partitioning, Cytoskeleton];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1063722395  223 GDVYVWGEVWS----DGISPDGvvnSTTVKIDVLipkpleSNVVldvhQIACGVRHIALVTRQGEVFTWEEEAGGRLGHG 298
Cdd:COG5184     17 GTVWCWGDNSYgqlgDGTTTDR---STPVRVPGL------SNVV----AVAAGGDHTCALKADGTVWCWGNNSYGQLGDG 83

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1063722395  299 IQVDVCRPKLVEflALTNIDFVACGEYHTCAVSTSGDLFTWGDGIHnvGLLGHGSDLSHWIPKRVSGPVEGlqVLSVACG 378
Cdd:COG5184     84 TTTDRTTPVKVP--GLTGVVAVAAGYYHSCALKSDGTVWCWGDNSS--GQLGDGTTTNRLTPVQVDAGLSG--VVAIAAG 157

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1063722395  379 TWHSALATANGKLFTFGDGAFGVLGHGDRESVSYPKEVKMLSGLKtlKVACGVWHTVAIvevmnqtgtsTSSRKLFTWGD 458
Cdd:COG5184    158 GYHTCALKSDGTVWCWGANSYGQLGDGTTTDRPTPVQVGGLSGVV--AVAAGGDHSCAL----------KSDGTVWCWGS 225

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1063722395  459 GDKNRLGHGNKETYLLPTCVSSLidYNFNQIACGHTFTVALTTSGHVFTMGGTSHGQLGSSNSDGKL-PCLVQDrlvGEF 537
Cdd:COG5184    226 NSSGQLGDGTTTDRATPVQVAGL--TGVVAIAAGGSHTCALKSDGTVWCWGDNSYGQLGDGTTTDRStPVKVPG---LSG 300

                          330       340       350       360
                   ....*....|....*....|....*....|....*....|...
gi 1063722395  538 VEEISCGDHHVAVLTSRSEVFTWGKGSNGRLGHGDKDDRKTPT 580
Cdd:COG5184    301 VVAVAAGSSHTCALLTDGTVWCWGDNAYGQLGDGTTTDRSTPV 343

Transcription factor regulating root and shoot growth via Pin3; The BREVIS RADIX (BRX) domain was characterized as being a transcription factor in plants regulating the extent of cell proliferation and elongation in the growth zone of the root. BRX is rate limiting for auxin-responsive gene-expression by mediating cross-talk with the brassino-steroid pathway. BRX has a ubiquitous, although quantitatively variable role in modulating the growth rate in both the root and the shoot. The family features a short region of alpha-helix, approximately 60 residues in length, which is found repeated up to three times. BRX is expressed in the vasculature and is rate-limiting for transcriptional auxin action.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1063722395  957 KELIEQFEPGVYVTYVLHKNGGKIFRRVRFSKRRFDEHQAEEWWNSKKDRLLKRY 1011
Cdd:pfam08381    2 REWVEQDEPGVYITLVILPDGTKELKRVRFSRRRFSEKQAEVWWEENRDRVYEKY 56

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        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1063722395   606 HKWVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAALAPTpgKPHRVCDACYTKLK 673
Cdd:smart00064    2 PHWIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLGIE--RPVRVCDDCYENLN 67

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 1063722395  617 CSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAALAptPGKPHRVCDACY 669
Cdd:cd00065      2 CMLCGKKFSLFRRRHHCRRCGRVFCSKCSSKKLPLPSFG--SGKPVRVCDSCY 52

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        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1063722395  608 WVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKkalKAALaPTPGKPHRVCDACY 669
Cdd:cd15721      1 WADDKEVTHCQQCEKEFSLSRRKHHCRNCGGIFCNSCSDN---TMPL-PSSAKPVRVCDTCY 58

FYVE domain found in protein containing both PH and FYVE domains 1 (phafin-1), 2 (phafin-2), and similar proteins; This family includes protein containing both PH and FYVE domains 1 (phafin-1) and 2 (phafin-2). Phafin-1 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. Phafin-2 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        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1063722395  608 WVSGADQSVCSGCRQA-FGFTRKRHNCYNCGLVHCHACSSKKALKAALAPtpgKPHRVCDACY 669
Cdd:cd15717      2 WVPDSEAPVCMHCKKTkFTAINRRHHCRKCGAVVCGACSSKKFLLPHQSS---KPLRVCDTCY 61

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 1063722395  615 SVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAALAPtPGKPHRVCDACY 669
Cdd:cd15760      6 SRCDVCRKKFGLFKRRHHCRNCGDSFCSEHSSRRIPLPHLGP-LGVPQRVCDRCF 59

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        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1063722395  612 ADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKalkaALAPTPG--KPHRVCDACYTKL 672
Cdd:cd15720      3 KDGDECHRCRVQFGVFQRKHHCRACGQVFCGKCSSKS----STIPKFGieKEVRVCDPCYEKL 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        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1063722395  607 KWVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACsskkaLKAALAPTP-GKPHRVCDACYTKL 672
Cdd:cd15739      3 RWQHEDDVDQCPNCKTPFSVGKRKHHCRHCGKIFCSDC-----LTKTVPSGPnRRPARVCDVCHTLL 64

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        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1063722395  608 WVSGADQSVCSGCRQA-FGFTRKRHNCYNCGLVHCHACSSKKALkaaLAPTPGKPHRVCDACYTKL 672
Cdd:cd15755      2 WVPDSEATVCMRCQKAkFTPVNRRHHCRKCGFVVCGPCSEKKFL---LPSQSSKPVRVCDFCYDLL 64

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 1063722395  608 WVSGADQSVCSGCRQA-FGFTRKRHNCYNCGLVHCHACSSKKALKAALAPtpgKPHRVCDACYTKL 672
Cdd:cd15754      2 WIPDKATDICMRCTQTnFSLLTRRHHCRKCGFVVCHECSRQRFLIPRLSP---KPVRVCSLCYRKL 64

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        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1063722395  608 WVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKalkaalAPTPGK----PHRVCDACY 669
Cdd:cd15733      1 WVPDHAASHCFGCDCEFWLAKRKHHCRNCGNVFCADCSNYK------LPIPDEqlydPVRVCNSCY 60

Pleckstrin homology domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1063722395   16 QALVSLKKGTQLLKYSRKGRP-KFRSFRLSPDETTLFW------------LSHGEEKgLKLATVSRILPGQRTAVFRR-- 80
Cdd:pfam16457    4 QRLNCLLEGAWFPKVRGRRRKkKYRFCRLSPNRKVLHYgdfeekptvdpsLESLPEK-IDLSDIKEVVTGKECPHVREsg 82

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 1063722395   81 -YLRPEKDYLSFSLIY-HNGDRSLDLICKDKAETEVWFAGLKSLI 123
Cdd:pfam16457   83 kKSKKTSSTLAFSLIYgADEYELLDFVAPSESVAAIWLDGLNMLL 127

Regulator of chromosome condensation (RCC1) repeat;

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                   ....*....|....*....|....*....|....*....|....*....|..
gi 1063722395  333 SGDLFTWGDGihNVGLLGHGSDLSHWIPKRVSGPvEGLQVLSVACGTWHSAL 384
Cdd:pfam00415    1 DGRVYTWGRN--DYGQLGLGTTENVLVPQKVEGL-SGNKVVQVACGGDHTVA 49

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.

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1063722395  608 WVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAALAPTpgKPHRVCDACYTKL 672
Cdd:cd15719      3 WVKDEGGDSCTGCSVRFSLTERRHHCRNCGQLFCSKCSRFESEIRRLRIS--RPVRVCQACYNIL 65

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.

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                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1063722395  608 WVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKkalKAALAPTPGKPHRVCDACY 669
Cdd:cd15743      3 WIPDSRVTMCMICTSEFTVTWRRHHCRACGKVVCGSCSSN---KAPLEYLKNKSARVCDECF 61

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.

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1063722395  607 KWVSGADQSVCSGCRQAFGF-TRKRHNCYNCGLVHCHACSSkkaLKAALAPTPGKPHRVCDACY 669
Cdd:cd15741      2 RWVRDNEVTMCMRCKEPFNAlTRRRHHCRACGYVVCWKCSD---YKATLEYDGNKLNRVCKHCY 62

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.

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                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1063722395  617 CSGCRQAFG-FTRKRHNCYNCGLVHCHACSSKKALKAALAPTPGKPHR----VCDACYTKL 672
Cdd:cd15723      2 CTGCGASFSvLLKKRRSCNNCGNAFCSRCCSKKVPRSVMGATAPAAQRetvfVCSGCNDKL 62

Regulator of chromosome condensation (RCC1) repeat;

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                   ....*....|....*....|....*....|....*....|....*....
gi 1063722395  282 GEVFTWEEEAGGRLGHGIQVDVCRPKLVEFLALTNIDFVACGEYHTCAV 330
Cdd:pfam00415    2 GRVYTWGRNDYGQLGLGTTENVLVPQKVEGLSGNKVVQVACGGDHTVAL 50

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).

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1063722395  608 WVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAalaptpgkphRVCDACYTKL 672
Cdd:cd15716      4 WVNDSDVPFCPDCGKKFNLARRRHHCRLCGSIMCNKCSQFLPLHI----------RCCHHCKDLL 58

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.

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                   ....*....|....*....|....*....|....*....|....*....|...
gi 1063722395  617 CSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAalAPTPGKPHRVCDACY 669
Cdd:cd15745      2 CAICAKAFSLFRRKYVCRLCGGVVCHSCSSEDLVLS--VPDTCIYLRVCKTCY 52

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.

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                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1063722395  616 VCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKkalKAALAPTPGKPHRVCDACYTKLK 673
Cdd:cd15742     11 MCMNCGSDFTLTLRRHHCHACGKIVCRNCSRN---KYPLKYLKDRPAKVCDGCFAELR 65

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.

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                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1063722395  608 WVSGADQSVCSGCRQAFGFTRKRHNCYNCGLVHCHACSSKKALKAalapTPGKPHRVCDACY 669
Cdd:cd15726      1 WQDDTDVTHCLDCKSEFSWMVRRHHCRLCGRIFCYACSNFYVLTA----HGGKKERCCKACF 58

Regulator of chromosome condensation (RCC1) repeat;

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                   ....*....|....*....|....*....|....*....|....*....|.
gi 1063722395  502 SGHVFTMGGTSHGQLGS-SNSDGKLPCLVQDrLVGEFVEEISCGDHHVAVL 551
Cdd:pfam00415    1 DGRVYTWGRNDYGQLGLgTTENVLVPQKVEG-LSGNKVVQVACGGDHTVAL 50

FYVE domain found in Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and FYVE-related domain 1 found in yeast protein VAC1 (Vac1p) and similar proteins; The family includes Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and protein VAC1 (Vac1p). 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. 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 FYVE domain in both Vps27p and Vac1p harbors a zinc-binding site composed of seven Cysteines and one Histidine, which is different from that of other FYVE domain containing proteins.

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                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1063722395  616 VCSGCRQAFGFTRKRHNCYNCGLVHC--HACSSKKALKAALAPTPGKPHRVCDACY 669
Cdd:cd15736      1 CCHTCSRTFNLNIRAHHCRKCGKLFCrrHLPNMIPLNLSAYDPRNGKWYRCCHSCF 56