Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720    726 QRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRYKDWE 805
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720    806 DPNgetPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASkHNMADVKELIPEFFYLPE 885
Cdd:pfam02138   81 DDD---PPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720    886 FLFNSNNFDLGCKQNGTKLGDVILPPWAKGDPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHLF 965
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 20521720    966 YEGQVDIYNINDPLKETATIGFINNFGQIPKQLFKKPHPPK 1006
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 20521720  564 EKIQHMYRCARVQGLDTSEGLLLFGKEHFYVIDGFTMTATREIRDIETlppnmhepiiprgaRQGPSQLKRTCSIFAYED 643
Cdd:cd01201    1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVINS--------------QKVLSYKEHLVFKWSLSD 66

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 20521720  644 IKEVHKRRYLLQPIAVEVFSGDGRNYLLAFQKGIRNKVYQRFLA 687
Cdd:cd01201   67 IREVHKRRYLLRDTALEIFFTDGTNYFLNFPSKERNDVYKKLLS 110

Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720    726 QRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRYKDWE 805
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720    806 DPNgetPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASkHNMADVKELIPEFFYLPE 885
Cdd:pfam02138   81 DDD---PPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720    886 FLFNSNNFDLGCKQNGTKLGDVILPPWAKGDPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHLF 965
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 20521720    966 YEGQVDIYNINDPLKETATIGFINNFGQIPKQLFKKPHPPK 1006
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 20521720  725 TQRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRYkdW 804
Cdd:cd06071    1 TKKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPIFPWVISDYTSEELDLNDPSTYRDLSKPIGALNKERLQLLKERY--E 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720  805 EDPNGETPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASKhNMADVKELIPEFFYLP 884
Cdd:cd06071   79 SDSDDSDPPFHYGSHYSNPAIVLYYLVRLEPFTTLHLSLQGGHFDAADRLFNSIPSSWRSASE-NPSDVKELIPEFYYLP 157

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720  885 EFLFNSNNFDLGcKQNGTKLGDVILPPWAKGdPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHL 964
Cdd:cd06071  158 EFFLNINKFDFG-KQDGEKVNDVELPPWAKS-PEEFIRKHREALESEYVSKNLHHWIDLIFGYKQRGEEAVKAKNVFHPL 235

                        250       260       270       280
                 ....*....|....*....|....*....|....*....|..
gi 20521720  965 FYEGQVDIYNINdpLKETATIGFINNFGQIPKQLFKKPHPPK 1006
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 20521720  564 EKIQHMYRCARVQGLDTSEGLLLFGKEHFYVIDGFTMTATREIRDIETlppnmhepiiprgaRQGPSQLKRTCSIFAYED 643
Cdd:cd01201    1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVINS--------------QKVLSYKEHLVFKWSLSD 66

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 20521720  644 IKEVHKRRYLLQPIAVEVFSGDGRNYLLAFQKGIRNKVYQRFLA 687
Cdd:cd01201   67 IREVHKRRYLLRDTALEIFFTDGTNYFLNFPSKERNDVYKKLLS 110

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 20521720   1479 DHWVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSE-IKRLKISSPVRVCQNCYYNLQH 1545
Cdd:pfam01363    1 PVWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISlLPELGSNKPVRVCDACYDTLQK 68

WD40 repeat [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720 1115 AICPNPKLVITGGTSTVVCVWEMGTSKekaktvtLKQALLGHTDTVTcataSLAY----HIIVSGSRDRTCIIWDLNKLS 1190
Cdd:COG2319  169 AFSPDGKLLASGSDDGTVRLWDLATGK-------LLRTLTGHTGAVR----SVAFspdgKLLASGSADGTVRLWDLATGK 237

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720 1191 FLTQLRGHRAPVSALCINeLTGDIVSCAGTY--IHVWSINGNPIVSvnTFTGRSQQIICCCMSEMNEWdtqnvIVTGHSD 1268
Cdd:COG2319  238 LLRTLTGHSGSVRSVAFS-PDGRLLASGSADgtVRLWDLATGELLR--TLTGHSGGVNSVAFSPDGKL-----LASGSDD 309

                        170       180
                 ....*....|....*....|....*
gi 20521720 1269 GVVRFWRMEFLQVPETPAPEPAEVL 1293
Cdd:COG2319  310 GTVRLWDLATGKLLRTLTGHTGAVR 334

Neurobeachin beta propeller domain; This entry represents the beta propeller domain found at the C-terminus of neurobeachin-like proteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720   1115 AICPNPKLVITGGTSTVVCVWEM--GTSKEKAKTVTLKQA--------------LLGHTDTVTCATASLAYHIIVSGSRD 1178
Cdd:pfam20426  131 AVTSDGSILATGSYDTTVMVWEVlrGRSSEKRSRNTQTEFprkdhviaetpfhiLCGHDDIITCLYVSVELDIVISGSKD 210

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720   1179 RTCIIWDLNKLSFLTQLRG-HRAPVSALCINElTGDIVSCAGT--YIHVWSINGNPIVSV 1235
Cdd:pfam20426  211 GTCIFHTLREGRYVRSIRHpSGCPLSKLVASR-HGRIVLYADDdlSLHLYSINGKHIASS 269

phosphatidylinositol kinase; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 20521720  1481 WVKD-EGGDSCSGCSVRF-----SLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVR--------VCQNCY 1540
Cdd:PTZ00303  453 WQKDdESSDSCPSCGRAFislsrPLGTRAHHCRSCGIRLCVFCITKRAHYSFAKLAKPGSsdeaeerlVCDTCY 526

Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720    726 QRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRYKDWE 805
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720    806 DPNgetPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASkHNMADVKELIPEFFYLPE 885
Cdd:pfam02138   81 DDD---PPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720    886 FLFNSNNFDLGCKQNGTKLGDVILPPWAKGDPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHLF 965
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 20521720    966 YEGQVDIYNINDPLKETATIGFINNFGQIPKQLFKKPHPPK 1006
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 20521720  725 TQRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRYkdW 804
Cdd:cd06071    1 TKKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPIFPWVISDYTSEELDLNDPSTYRDLSKPIGALNKERLQLLKERY--E 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720  805 EDPNGETPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASKhNMADVKELIPEFFYLP 884
Cdd:cd06071   79 SDSDDSDPPFHYGSHYSNPAIVLYYLVRLEPFTTLHLSLQGGHFDAADRLFNSIPSSWRSASE-NPSDVKELIPEFYYLP 157

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720  885 EFLFNSNNFDLGcKQNGTKLGDVILPPWAKGdPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHL 964
Cdd:cd06071  158 EFFLNINKFDFG-KQDGEKVNDVELPPWAKS-PEEFIRKHREALESEYVSKNLHHWIDLIFGYKQRGEEAVKAKNVFHPL 235

                        250       260       270       280
                 ....*....|....*....|....*....|....*....|..
gi 20521720  965 FYEGQVDIYNINdpLKETATIGFINNFGQIPKQLFKKPHPPK 1006
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 20521720  564 EKIQHMYRCARVQGLDTSEGLLLFGKEHFYVIDGFTMTATREIRDIETlppnmhepiiprgaRQGPSQLKRTCSIFAYED 643
Cdd:cd01201    1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVINS--------------QKVLSYKEHLVFKWSLSD 66

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 20521720  644 IKEVHKRRYLLQPIAVEVFSGDGRNYLLAFQKGIRNKVYQRFLA 687
Cdd:cd01201   67 IREVHKRRYLLRDTALEIFFTDGTNYFLNFPSKERNDVYKKLLS 110

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 20521720   1479 DHWVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSE-IKRLKISSPVRVCQNCYYNLQH 1545
Cdd:pfam01363    1 PVWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISlLPELGSNKPVRVCDACYDTLQK 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 20521720 1114 CAICPNPKLVITGGTSTVVCVWEMGTSKekaktvtLKQALLGHTDTVTCATASLAYHIIVSGSRDRTCIIWDLNKLSFLT 1193
Cdd:cd00200   99 VAFSPDGRILSSSSRDKTIKVWDVETGK-------CLTTLRGHTDWVNSVAFSPDGTFVASSSQDGTIKLWDLRTGKCVA 171

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720 1194 QLRGHRAPVSALCINELTGDIVSCAGTY-IHVWSINGnpIVSVNTFTGRSQQIICCCMSEMNEWdtqnvIVTGHSDGVVR 1272
Cdd:cd00200  172 TLTGHTGEVNSVAFSPDGEKLLSSSSDGtIKLWDLST--GKCLGTLRGHENGVNSVAFSPDGYL-----LASGSEDGTIR 244

                 ....*
gi 20521720 1273 FWRME 1277
Cdd:cd00200  245 VWDLR 249

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
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 20521720 1487 GDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCYYNL 1543
Cdd:cd15720    5 GDECHRCRVQFGVFQRKHHCRACGQVFCGKCSSKSSTIPKFGIEKEVRVCDPCYEKL 61

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 20521720 1481 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 1540
Cdd:cd15731    5 WVPDEACPQCMACSAPFTVLRRRHHCRNCGKIFCSRCSSNSVPLPRYGQMKPVRVCNHCF 64

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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 20521720 1480 HWVKDeggDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQseiKRL----KISSPVRVCQNCY 1540
Cdd:cd15760    1 HWKPD---SRCDVCRKKFGLFKRRHHCRNCGDSFCSEHSSRR---IPLphlgPLGVPQRVCDRCF 59

FYVE domain found in ankyrin repeat and FYVE domain-containing protein 1 (ANFY1) and similar proteins; ANFY1, also termed ankyrin repeats hooked to a zinc finger motif (Ankhzn), is a novel cytoplasmic protein that belongs to a new group of double zinc finger proteins involved in vesicle or protein transport. It is ubiquitously expressed in a spatiotemporal-specific manner and is located on endosomes. ANFY1 contains an N-terminal coiled-coil region and a BTB/POZ domain, ankyrin repeats in the middle, and a C-terminal FYVE domain.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 20521720 1487 GDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 1540
Cdd:cd15728    7 GDYCYECGVKFGITTRKHHCRHCGRLLCSKCSTKEVPIIKFDLNKPVRVCDVCF 60

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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720 1481 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 1540
Cdd:cd15727    4 WVPDKECPVCMSCKKKFDFFKRRHHCRRCGKCFCSDCCSNKVPLPRMCFVDPVRVCNECA 63

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 20521720 1149 LKQALLGHTDTVTCATASLAYHIIVSGSRDRTCIIWDLNKLSFLTQLRGHRAPV---SALCINELtgdIVSCA--GTyIH 1223
Cdd:cd00200    1 LRRTLKGHTGGVTCVAFSPDGKLLATGSGDGTIKVWDLETGELLRTLKGHTGPVrdvAASADGTY---LASGSsdKT-IR 76

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 20521720 1224 VWSINGNPIVSvnTFTGRSQQIICCCMSEMNEWdtqnvIVTGHSDGVVRFWRME 1277
Cdd:cd00200   77 LWDLETGECVR--TLTGHTSYVSSVAFSPDGRI-----LSSSSRDKTIKVWDVE 123

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 20521720 1481 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKiSSPVRVCQNCY 1540
Cdd:cd15729    7 WVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLEYLD-NKEARVCVPCY 65

WD40 repeat [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720 1115 AICPNPKLVITGGTSTVVCVWEMGTSKekaktvtLKQALLGHTDTVTcataSLAY----HIIVSGSRDRTCIIWDLNKLS 1190
Cdd:COG2319  169 AFSPDGKLLASGSDDGTVRLWDLATGK-------LLRTLTGHTGAVR----SVAFspdgKLLASGSADGTVRLWDLATGK 237

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720 1191 FLTQLRGHRAPVSALCINeLTGDIVSCAGTY--IHVWSINGNPIVSvnTFTGRSQQIICCCMSEMNEWdtqnvIVTGHSD 1268
Cdd:COG2319  238 LLRTLTGHSGSVRSVAFS-PDGRLLASGSADgtVRLWDLATGELLR--TLTGHSGGVNSVAFSPDGKL-----LASGSDD 309

                        170       180
                 ....*....|....*....|....*
gi 20521720 1269 GVVRFWRMEFLQVPETPAPEPAEVL 1293
Cdd:COG2319  310 GTVRLWDLATGKLLRTLTGHTGAVR 334

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 20521720 1481 WVKDEGGDSCSGCS-VRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKiSSPVRVCQNCYYNL 1543
Cdd:cd15754    2 WIPDKATDICMRCTqTNFSLLTRRHHCRKCGFVVCHECSRQRFLIPRLS-PKPVRVCSLCYRKL 64

WD40 repeat [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720 1115 AICPNPKLVITGGTSTVVCVWEMGTSKekaktvtLKQALLGHTDTVTcataSLAY----HIIVSGSRDRTCIIWDLNKLS 1190
Cdd:COG2319  127 AFSPDGKTLASGSADGTVRLWDLATGK-------LLRTLTGHSGAVT----SVAFspdgKLLASGSDDGTVRLWDLATGK 195

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720 1191 FLTQLRGHRAPVSALCINElTGDIVSCAGT--YIHVWSINGNPIVSvnTFTGRSQQIICCCMSEmnewDTQnVIVTGHSD 1268
Cdd:COG2319  196 LLRTLTGHTGAVRSVAFSP-DGKLLASGSAdgTVRLWDLATGKLLR--TLTGHSGSVRSVAFSP----DGR-LLASGSAD 267

                 ....*..
gi 20521720 1269 GVVRFWR 1275
Cdd:COG2319  268 GTVRLWD 274

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 20521720 1480 HWVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 1540
Cdd:cd15725    1 YWMPDSSCKECYECSEKFTTFRRRHHCRLCGQIFCSRCCNQEIPGKFIGYPGDLRVCTYCC 61

FYVE domain found in myotubularin-related protein 3 (MTMR3) and similar proteins; MTMR3, also termed Myotubularin-related phosphatase 3, or FYVE domain-containing dual specificity protein phosphatase 1 (FYVE-DSP1), or zinc finger FYVE domain-containing protein 10, is a ubiquitously expressed phosphoinositide 3-phosphatase specific for phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) and PIKfyve, which produces PtdIns(3,5)P2 from PtdIns3P. It regulates cell migration through modulating phosphatidylinositol 5-phosphate (PtdIns5P) levels. MTMR3 contains an N-terminal PH-GRAM (PH-G) domain, a MTM phosphatase domain, a coiled-coil region, and a C-terminal FYVE domain. Unlike conventional FYVE domains, the FYVE domain of MTMR3 neither confers endosomal localization nor binds to PtdIns3P. It is also not required for the enzyme activity of MTMR3. In contrast, the PH-G domain binds phosphoinositides.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 20521720 1481 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 1540
Cdd:cd15732    2 WVPDHLAASCYGCEREFWLASRKHHCRNCGNVFCGSCCNQKLPVPSQQLFEPSRVCKSCF 61

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 20521720    632 LKRTCSIFAYEDIKEVHKRRYLLQPIAVEVFSGDGRNYLLAFQ-KGIRNKVYQR 684
Cdd:pfam14844   44 DKPKHKRWPISDIKEVHLRRYLLRDTALEIFLIDRTSLFFNFPdTGTRRKVYRK 97

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 20521720 1481 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKiSSPVRVCQNCY 1540
Cdd:cd15743    3 WIPDSRVTMCMICTSEFTVTWRRHHCRACGKVVCGSCSSNKAPLEYLK-NKSARVCDECF 61