Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261  2589 QRWLSGNISNFQYLMHLNTLAGRCYNDLSQYPIFPWVLADYTSSQLDFNNISTFRDFSKPMGAQSPDRLEQFLKRFREWD 2668
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261  2669 DPsgeTPPYMYGTHYSSAMIVVSYLVRLEPFTQQFLSLQGGHFDLADRMFHSVGDAWTSASrNNMADVKELIPEFFTLPE 2748
Cdd:pfam02138   81 DD---DPPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261  2749 MFTNTNHFDLGVKQNGIHVNDVLLPAWCHGDPREFIRLHRQALESDYVSSHLHEWIDLIFGYKQNGEEAVKNSNLFHHLF 2828
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 392901261  2829 YEGSVDFERIDDPLTRNATIGFVNNFGQIPTQLFKKPHPQK 2869
Cdd:pfam02138  237 YEGSVDLDSIKDPVERDAIEAQIKNFGQTPKQLFTKPHPPR 277

Pleckstrin homology domain in BEACH domain containing proteins; The BEACH domain is present in several eukaroyotic proteins CHS, neurobeachin (Nbea), LRBA (also called BGL, beige-like, or CDC4L), FAN, KIAA1607, and LvsA-LvsF. CHS is a rare, autosomal recessive disorder that can cause severe immunodeficiency and albinism in mammals and beige is the name for the CHS disease in mice. The CHS disease is associated with the presence of giant, perinuclear vesicles (lysosomes, melanosomes, and others) and CHS protein is thought to play an important role in the fusion, fission, or trafficking of these vesicles. All BEACH proteins contain the following domains: PH, BEACH, and WD40. The WD40 domain is involved in mediating protein-protein interactions involved in targeting proteins to subcellular compartments. The combined PH-BEACH motifs may present a single continuous structural unit involved in protein binding. Some members have an additional N-terminal Laminin G-like (LamG) domains Ca++ mediated receptors or an additional C-terminal FYVE zinc-binding domain which targets proteins to membrane lipids via interaction with phosphatidylinositol-3-phosphate, PI3P. 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 392901261 2421 EQLHSMFRCARIQGLETAEGLLLFGRDHFYVVDGFTLLKTKEIRDLdflsqemhdpivpypaTGATQPPKSSRLCSKFSY 2500
Cdd:cd01201     1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVI----------------NSQKVLSYKEHLVFKWSL 64

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 392901261 2501 NMIREVHKRRYLLQPIALEVFSSDGRNYLLAFPKKIRDRVFDKLTSMA 2548
Cdd:cd01201    65 SDIREVHKRRYLLRDTALEIFFTDGTNYFLNFPSKERNDVYKKLLSLL 112

Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261  2589 QRWLSGNISNFQYLMHLNTLAGRCYNDLSQYPIFPWVLADYTSSQLDFNNISTFRDFSKPMGAQSPDRLEQFLKRFREWD 2668
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261  2669 DPsgeTPPYMYGTHYSSAMIVVSYLVRLEPFTQQFLSLQGGHFDLADRMFHSVGDAWTSASrNNMADVKELIPEFFTLPE 2748
Cdd:pfam02138   81 DD---DPPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261  2749 MFTNTNHFDLGVKQNGIHVNDVLLPAWCHGDPREFIRLHRQALESDYVSSHLHEWIDLIFGYKQNGEEAVKNSNLFHHLF 2828
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 392901261  2829 YEGSVDFERIDDPLTRNATIGFVNNFGQIPTQLFKKPHPQK 2869
Cdd:pfam02138  237 YEGSVDLDSIKDPVERDAIEAQIKNFGQTPKQLFTKPHPPR 277

BEACH (Beige and Chediak-Higashi) domains, implicated in membrane trafficking, are present in a family of proteins conserved throughout eukaryotes. This group contains human lysosomal trafficking regulator (LYST), LPS-responsive and beige-like anchor (LRBA) and neurobeachin. Disruption of LYST leads to Chediak-Higashi syndrome, characterized by severe immunodeficiency, albinism, poor blood coagulation and neurologic problems. Neurobeachin is a candidate gene linked to autism. LBRA seems to be upregulated in several cancer types. It has been shown that the BEACH domain itself is important for the function of these proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 2588 TQRWLSGNISNFQYLMHLNTLAGRCYNDLSQYPIFPWVLADYTSSQLDFNNISTFRDFSKPMGAQSPDRLEQFLKRFreW 2667
Cdd:cd06071     1 TKKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPIFPWVISDYTSEELDLNDPSTYRDLSKPIGALNKERLQLLKERY--E 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 2668 DDPSGETPPYMYGTHYSSAMIVVSYLVRLEPFTQQFLSLQGGHFDLADRMFHSVGDAWTSASrNNMADVKELIPEFFTLP 2747
Cdd:cd06071    79 SDSDDSDPPFHYGSHYSNPAIVLYYLVRLEPFTTLHLSLQGGHFDAADRLFNSIPSSWRSAS-ENPSDVKELIPEFYYLP 157

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 2748 EMFTNTNHFDLGvKQNGIHVNDVLLPAWCHGdPREFIRLHRQALESDYVSSHLHEWIDLIFGYKQNGEEAVKNSNLFHHL 2827
Cdd:cd06071   158 EFFLNINKFDFG-KQDGEKVNDVELPPWAKS-PEEFIRKHREALESEYVSKNLHHWIDLIFGYKQRGEEAVKAKNVFHPL 235

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|..
gi 392901261 2828 FYEGSVDFERIDdpLTRNATIGFVNNFGQIPTQLFKKPHPQK 2869
Cdd:cd06071   236 TYEGSVDLDSID--VEREAIEAQINNFGQTPVQLFTKPHPKR 275

Pleckstrin homology domain in BEACH domain containing proteins; The BEACH domain is present in several eukaroyotic proteins CHS, neurobeachin (Nbea), LRBA (also called BGL, beige-like, or CDC4L), FAN, KIAA1607, and LvsA-LvsF. CHS is a rare, autosomal recessive disorder that can cause severe immunodeficiency and albinism in mammals and beige is the name for the CHS disease in mice. The CHS disease is associated with the presence of giant, perinuclear vesicles (lysosomes, melanosomes, and others) and CHS protein is thought to play an important role in the fusion, fission, or trafficking of these vesicles. All BEACH proteins contain the following domains: PH, BEACH, and WD40. The WD40 domain is involved in mediating protein-protein interactions involved in targeting proteins to subcellular compartments. The combined PH-BEACH motifs may present a single continuous structural unit involved in protein binding. Some members have an additional N-terminal Laminin G-like (LamG) domains Ca++ mediated receptors or an additional C-terminal FYVE zinc-binding domain which targets proteins to membrane lipids via interaction with phosphatidylinositol-3-phosphate, PI3P. 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 392901261 2421 EQLHSMFRCARIQGLETAEGLLLFGRDHFYVVDGFTLLKTKEIRDLdflsqemhdpivpypaTGATQPPKSSRLCSKFSY 2500
Cdd:cd01201     1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVI----------------NSQKVLSYKEHLVFKWSL 64

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 392901261 2501 NMIREVHKRRYLLQPIALEVFSSDGRNYLLAFPKKIRDRVFDKLTSMA 2548
Cdd:cd01201    65 SDIREVHKRRYLLRDTALEIFFTDGTNYFLNFPSKERNDVYKKLLSLL 112

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 392901261  3283 DHWVQDVTRQRCDDCEHKFTLADRKHHCRNCGQIFCSTCS-RFESHITRMNISRPVRVCRKCFQRLQQ 3349
Cdd:pfam01363    1 PVWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSsKKISLLPELGSNKPVRVCDACYDTLQK 68

PH domain associated with Beige/BEACH; This PH domain is found in proteins containing the Beige/BEACH domain (pfam02138), it immediately precedes the Beige/BEACH domain.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 392901261  2489 PKSSRLCSKFSYNMIREVHKRRYLLQPIALEVFSSDGRNYLLAFP-KKIRDRVFDKL 2544
Cdd:pfam14844   42 GYDKPKHKRWPISDIKEVHLRRYLLRDTALEIFLIDRTSLFFNFPdTGTRRKVYRKL 98

WD40 repeats; Note that these repeats are permuted with respect to the structural repeats (blades) of the beta propeller domain.

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|
gi 392901261   2999 SMKKLSVLNGHSDAITCLVSCQSHAVLVSASRDLTVLVWH 3038
Cdd:smart00320    1 SGELLKTLKGHTGPVTSVAFSPDGKYLASGSDDGTIKLWD 40

phosphatidylinositol kinase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 3288 DVTRQRCDDCEHKFT-----LADRKHHCRNCGQIFCSTCSRFESHITRMNISRPVR--------VCRKCFQRLQQSSNLH 3354
Cdd:PTZ00303  457 DESSDSCPSCGRAFIslsrpLGTRAHHCRSCGIRLCVFCITKRAHYSFAKLAKPGSsdeaeerlVCDTCYKEYETVSQLH 536

                  ..
gi 392901261 3355 NL 3356
Cdd:PTZ00303  537 YL 538

Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261  2589 QRWLSGNISNFQYLMHLNTLAGRCYNDLSQYPIFPWVLADYTSSQLDFNNISTFRDFSKPMGAQSPDRLEQFLKRFREWD 2668
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261  2669 DPsgeTPPYMYGTHYSSAMIVVSYLVRLEPFTQQFLSLQGGHFDLADRMFHSVGDAWTSASrNNMADVKELIPEFFTLPE 2748
Cdd:pfam02138   81 DD---DPPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261  2749 MFTNTNHFDLGVKQNGIHVNDVLLPAWCHGDPREFIRLHRQALESDYVSSHLHEWIDLIFGYKQNGEEAVKNSNLFHHLF 2828
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 392901261  2829 YEGSVDFERIDDPLTRNATIGFVNNFGQIPTQLFKKPHPQK 2869
Cdd:pfam02138  237 YEGSVDLDSIKDPVERDAIEAQIKNFGQTPKQLFTKPHPPR 277

BEACH (Beige and Chediak-Higashi) domains, implicated in membrane trafficking, are present in a family of proteins conserved throughout eukaryotes. This group contains human lysosomal trafficking regulator (LYST), LPS-responsive and beige-like anchor (LRBA) and neurobeachin. Disruption of LYST leads to Chediak-Higashi syndrome, characterized by severe immunodeficiency, albinism, poor blood coagulation and neurologic problems. Neurobeachin is a candidate gene linked to autism. LBRA seems to be upregulated in several cancer types. It has been shown that the BEACH domain itself is important for the function of these proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 2588 TQRWLSGNISNFQYLMHLNTLAGRCYNDLSQYPIFPWVLADYTSSQLDFNNISTFRDFSKPMGAQSPDRLEQFLKRFreW 2667
Cdd:cd06071     1 TKKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPIFPWVISDYTSEELDLNDPSTYRDLSKPIGALNKERLQLLKERY--E 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 2668 DDPSGETPPYMYGTHYSSAMIVVSYLVRLEPFTQQFLSLQGGHFDLADRMFHSVGDAWTSASrNNMADVKELIPEFFTLP 2747
Cdd:cd06071    79 SDSDDSDPPFHYGSHYSNPAIVLYYLVRLEPFTTLHLSLQGGHFDAADRLFNSIPSSWRSAS-ENPSDVKELIPEFYYLP 157

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 2748 EMFTNTNHFDLGvKQNGIHVNDVLLPAWCHGdPREFIRLHRQALESDYVSSHLHEWIDLIFGYKQNGEEAVKNSNLFHHL 2827
Cdd:cd06071   158 EFFLNINKFDFG-KQDGEKVNDVELPPWAKS-PEEFIRKHREALESEYVSKNLHHWIDLIFGYKQRGEEAVKAKNVFHPL 235

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|..
gi 392901261 2828 FYEGSVDFERIDdpLTRNATIGFVNNFGQIPTQLFKKPHPQK 2869
Cdd:cd06071   236 TYEGSVDLDSID--VEREAIEAQINNFGQTPVQLFTKPHPKR 275

Pleckstrin homology domain in BEACH domain containing proteins; The BEACH domain is present in several eukaroyotic proteins CHS, neurobeachin (Nbea), LRBA (also called BGL, beige-like, or CDC4L), FAN, KIAA1607, and LvsA-LvsF. CHS is a rare, autosomal recessive disorder that can cause severe immunodeficiency and albinism in mammals and beige is the name for the CHS disease in mice. The CHS disease is associated with the presence of giant, perinuclear vesicles (lysosomes, melanosomes, and others) and CHS protein is thought to play an important role in the fusion, fission, or trafficking of these vesicles. All BEACH proteins contain the following domains: PH, BEACH, and WD40. The WD40 domain is involved in mediating protein-protein interactions involved in targeting proteins to subcellular compartments. The combined PH-BEACH motifs may present a single continuous structural unit involved in protein binding. Some members have an additional N-terminal Laminin G-like (LamG) domains Ca++ mediated receptors or an additional C-terminal FYVE zinc-binding domain which targets proteins to membrane lipids via interaction with phosphatidylinositol-3-phosphate, PI3P. 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 392901261 2421 EQLHSMFRCARIQGLETAEGLLLFGRDHFYVVDGFTLLKTKEIRDLdflsqemhdpivpypaTGATQPPKSSRLCSKFSY 2500
Cdd:cd01201     1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVI----------------NSQKVLSYKEHLVFKWSL 64

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 392901261 2501 NMIREVHKRRYLLQPIALEVFSSDGRNYLLAFPKKIRDRVFDKLTSMA 2548
Cdd:cd01201    65 SDIREVHKRRYLLRDTALEIFFTDGTNYFLNFPSKERNDVYKKLLSLL 112

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 392901261  3283 DHWVQDVTRQRCDDCEHKFTLADRKHHCRNCGQIFCSTCS-RFESHITRMNISRPVRVCRKCFQRLQQ 3349
Cdd:pfam01363    1 PVWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSsKKISLLPELGSNKPVRVCDACYDTLQK 68

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 392901261 3285 WVQDVTRQRCDDCEHKFTLADRKHHCRNCGQIFCSTCSRFESHITRMNISRPVRVCRKCF 3344
Cdd:cd15733     1 WVPDHAASHCFGCDCEFWLAKRKHHCRNCGNVFCADCSNYKLPIPDEQLYDPVRVCNSCY 60

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 392901261 3293 RCDDCEHKFTLADRKHHCRNCGQIFCSTCSRFESHITRMNISRPVRVCRKCF 3344
Cdd:cd00065     1 RCMLCGKKFSLFRRRHHCRRCGRVFCSKCSSKKLPLPSFGSGKPVRVCDSCY 52

FYVE domain found in zinc finger FYVE domain-containing protein 21 (ZF21) and similar proteins; ZF21 is phosphoinositide-binding protein that functions as a regulator of focal adhesions and cell movement through interaction with focal adhesion kinase. It can also bind to the cytoplasmic tail of membrane type 1 matrix metalloproteinase, a potent invasion-promoting protease, and play a key role in regulating multiple aspects of cancer cell migration and invasion. ZF21 contains a FYVE domain, which corresponds to this model.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 392901261 3285 WVQDVTRQRCDDCEHKFTLADRKHHCRNCGQIFCSTCSRFESHITRMNISRPVRVCRKC 3343
Cdd:cd15727     4 WVPDKECPVCMSCKKKFDFFKRRHHCRRCGKCFCSDCCSNKVPLPRMCFVDPVRVCNEC 62

FYVE domain found in early endosome antigen 1 (EEA1) and similar proteins; EEA1, also termed endosome-associated protein p162, or zinc finger FYVE domain-containing protein 2, is an essential component of the endosomal fusion machinery and required for the fusion and maturation of early endosomes in endocytosis. It forms a parallel coiled-coil homodimer in cells. EEA1 serves as the p97 ATPase substrate and the p97 ATPase may regulate the size of early endosomes by governing the oligomeric state of EEA1. It can interact with the GTP-bound form of Rab22a and be involved in endosomal membrane trafficking. EEA1 also functions as an obligate scaffold for angiotensin II-induced Akt activation in early endosomes. It can be phosphorylated by p38 mitogen-activated protein kinase (MAPK) and further regulate mu opioid receptor endocytosis. EEA1 consists of an N-terminal C2H2 Zn2+ finger, four long heptad repeats, and a C-terminal region containing a calmodulin binding (IQ) motif, a Rab5 interaction site, and a FYVE domain. This model corresponds to the FYVE domain that is responsible for binding phosphatidyl inositol-3-phosphate (PtdIns3P or PI3P) on the membrane.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 3285 WVQDVTRQRCDDCEHKFTLADRKHHCRNCGQIFCSTCSRFESHITRMNisRPVRVCRKCF 3344
Cdd:cd15730     3 WADDEEVQNCMACGKGFSVTVRKHHCRQCGNIFCNECSSKTATTPSSK--KPVRVCDACF 60

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 392901261 3284 HWVQDVTRQRCDDCEHKFTLADRKHHCRNCGQIFCSTCSRFESHITRMNISRPVRVCRKCFQ 3345
Cdd:cd15725     1 YWMPDSSCKECYECSEKFTTFRRRHHCRLCGQIFCSRCCNQEIPGKFIGYPGDLRVCTYCCK 62

WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 2943 DRSVRMGQIDNDKSVCVHEMCEVDEMTCAAAGDETTLFCGNTSGCITVWKVNNKplsmKKLSVLNGHSDAITCLVSCQSH 3022
Cdd:cd00200    72 DKTIRLWDLETGECVRTLTGHTSYVSSVAFSPDGRILSSSSRDKTIKVWDVETG----KCLTTLRGHTDWVNSVAFSPDG 147

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 3023 AVLVSASRDLTVLVWHLSEMFLIRQLPKHPHAVLAVAVNDATGDIATACS-TLLHVWTLN-GELLAVLNTCDVApaidpq 3100
Cdd:cd00200   148 TFVASSSQDGTIKLWDLRTGKCVATLTGHTGEVNSVAFSPDGEKLLSSSSdGTIKLWDLStGKCLGTLRGHENG------ 221

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*...
gi 392901261 3101 qmIISLAFSTmnewdNDNVIMCGTSDGIVKIYSCVVFENDGSVSEHPA 3148
Cdd:cd00200   222 --VNSVAFSP-----DGYLLASGSEDGTIRVWDLRTGECVQTLSGHTN 262

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 392901261 3285 WVQDVTRQRCDDCEHKFTLADRKHHCRNCGQIFCSTCSRFESHITRMNiSRPVRVCRKCFQRL 3347
Cdd:cd15729     7 WVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLEYLD-NKEARVCVPCYQTL 68

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        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 392901261 3285 WVQDVTRQRCDDCEHKFTLADRKHHCRNCGQIFCSTCSRFeshitrmnISRPVRVCRKCFQRL 3347
Cdd:cd15716     4 WVNDSDVPFCPDCGKKFNLARRRHHCRLCGSIMCNKCSQF--------LPLHIRCCHHCKDLL 58

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 392901261 3294 CDDCEHKFTLADRKHHCRNCGQIFCSTCSRFESHITRMNISRPVRVCRKCF 3344
Cdd:cd15735     9 CMRCRTAFTFTNRKHHCRNCGGVFCQQCSSKSLPLPHFGINQPVRVCDGCY 59

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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 3285 WVQDVTRQRCDDCEHKFTLADRKHHCRNCGQIFCSTCSRFESHITRMNISRPVRVCRKCF 3344
Cdd:cd15734     2 WVPDSEIKECSVCKRPFSPRLSKHHCRACGQGVCDDCSKNRRPVPSRGWDHPVRVCDPCA 61

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 392901261 3285 WVQDVTRQRCDDC-EHKFTLADRKHHCRNCGQIFCSTCSRFESHITRMNiSRPVRVCRKCFQRL 3347
Cdd:cd15754     2 WIPDKATDICMRCtQTNFSLLTRRHHCRKCGFVVCHECSRQRFLIPRLS-PKPVRVCSLCYRKL 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 392901261 3285 WVQDVTRQRCDDCEH-KFTLADRKHHCRNCGQIFCSTCSRfESHITRMNISRPVRVCRKCFQRL 3347
Cdd:cd15755     2 WVPDSEATVCMRCQKaKFTPVNRRHHCRKCGFVVCGPCSE-KKFLLPSQSSKPVRVCDFCYDLL 64

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 392901261 3285 WVQDVTRQRCDDCEHKFTLADRKHHCRNCGQIFCSTCsrfeshITRMNIS----RPVRVCRKCFQRLQQSS 3351
Cdd:cd15739     4 WQHEDDVDQCPNCKTPFSVGKRKHHCRHCGKIFCSDC------LTKTVPSgpnrRPARVCDVCHTLLVKDS 68

WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 2969 TCAAAGDETTLFC-GNTSGCITVWKVNNkplsMKKLSVLNGHSDAITCLVSCQSHAVLVSASRDLTVLVWHLSEMFLIRQ 3047
Cdd:cd00200    13 TCVAFSPDGKLLAtGSGDGTIKVWDLET----GELLRTLKGHTGPVRDVAASADGTYLASGSSDKTIRLWDLETGECVRT 88

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 3048 LPKHPHAVLAVAVNDaTGDIATACSTL--LHVWTL-NGELLAVLN--TCDVApaidpqqmiiSLAFSTmnewdNDNVIMC 3122
Cdd:cd00200    89 LTGHTSYVSSVAFSP-DGRILSSSSRDktIKVWDVeTGKCLTTLRghTDWVN----------SVAFSP-----DGTFVAS 152

                         170
                  ....*....|.
gi 392901261 3123 GTSDGIVKIYS 3133
Cdd:cd00200   153 SSQDGTIKLWD 163

WD40 repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 2975 DETTLFCGNTSGCITVWKVNNKPLsmkkLSVLNGHSDAITCLVSCQSHAVLVSASRDLTVLVWHLSEMFLIRQLPKHPHA 3054
Cdd:COG2319   131 DGKTLASGSADGTVRLWDLATGKL----LRTLTGHSGAVTSVAFSPDGKLLASGSDDGTVRLWDLATGKLLRTLTGHTGA 206

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392901261 3055 VLAVAVNdATGD-IATACS-TLLHVWTLN-GELLAVLNtcdvapaiDPQQMIISLAFStmnewDNDNVIMCGTSDGIVKI 3131
Cdd:COG2319   207 VRSVAFS-PDGKlLASGSAdGTVRLWDLAtGKLLRTLT--------GHSGSVRSVAFS-----PDGRLLASGSADGTVRL 272

                  ..
gi 392901261 3132 YS 3133
Cdd:COG2319   273 WD 274

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 392901261 3296 DCEHKFTLADRKHHCRNCGQIFCSTC----SRFESHITRmnisRPVRVCRKCF 3344
Cdd:cd15738    13 SCSTPFDHFSKKHHCWRCGNVFCTRCidkqRALPGHLSQ----RPVPVCRACY 61