Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2698 QRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRFKDWE 2777
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2778 DPNgetPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASkHNMADVKELIPEFFYLPE 2857
Cdd:pfam02138   81 DDD---PPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2858 FLFNSNNFDLGCKQNGTKLGDVILPPWAKGDPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHLF 2937
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 1910339379 2938 YEGQVDIYNINDPLKETATIGFINNFGQIPKQLFKKPHPPK 2978
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 1910339379 2536 EKIQHMYRCARVQGLDTSEGLLLFGKEHFYVIDGFTMTATREIRDIETlppnmhepiiprgaRQGPSQLKRTCSSFAYED 2615
Cdd:cd01201      1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVINS--------------QKVLSYKEHLVFKWSLSD 66

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....
gi 1910339379 2616 IKEVHKRRYLLQPIAVEVFSGDGRNYLLAFQKGIRNKVYQRFLA 2659
Cdd:cd01201     67 IREVHKRRYLLRDTALEIFFTDGTNYFLNFPSKERNDVYKKLLS 110

Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2698 QRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRFKDWE 2777
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2778 DPNgetPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASkHNMADVKELIPEFFYLPE 2857
Cdd:pfam02138   81 DDD---PPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2858 FLFNSNNFDLGCKQNGTKLGDVILPPWAKGDPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHLF 2937
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 1910339379 2938 YEGQVDIYNINDPLKETATIGFINNFGQIPKQLFKKPHPPK 2978
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 1910339379 2697 TQRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRFkdW 2776
Cdd:cd06071      1 TKKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPIFPWVISDYTSEELDLNDPSTYRDLSKPIGALNKERLQLLKERY--E 78

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2777 EDPNGETPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASKhNMADVKELIPEFFYLP 2856
Cdd:cd06071     79 SDSDDSDPPFHYGSHYSNPAIVLYYLVRLEPFTTLHLSLQGGHFDAADRLFNSIPSSWRSASE-NPSDVKELIPEFYYLP 157

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2857 EFLFNSNNFDLGcKQNGTKLGDVILPPWAKGdPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHL 2936
Cdd:cd06071    158 EFFLNINKFDFG-KQDGEKVNDVELPPWAKS-PEEFIRKHREALESEYVSKNLHHWIDLIFGYKQRGEEAVKAKNVFHPL 235

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|..
gi 1910339379 2937 FYEGQVDIYNINdpLKETATIGFINNFGQIPKQLFKKPHPPK 2978
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 1910339379 2536 EKIQHMYRCARVQGLDTSEGLLLFGKEHFYVIDGFTMTATREIRDIETlppnmhepiiprgaRQGPSQLKRTCSSFAYED 2615
Cdd:cd01201      1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVINS--------------QKVLSYKEHLVFKWSLSD 66

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....
gi 1910339379 2616 IKEVHKRRYLLQPIAVEVFSGDGRNYLLAFQKGIRNKVYQRFLA 2659
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 1910339379 3452 DHWVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSE-IKRLKISSPVRVCQNCYYNLQH 3518
Cdd:pfam01363    1 PVWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISlLPELGSNKPVRVCDACYDTLQK 68

WD40 repeat [General function prediction only];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 3087 AICPNPKLVITGGTSTVVCVWEMGTSKEKaKTLTlkqallGHTDTVTCATASLAYHIIVSGSRDRTCIIWDLNKLSFLTQ 3166
Cdd:COG2319    211 AFSPDGKLLASGSADGTVRLWDLATGKLL-RTLT------GHSGSVRSVAFSPDGRLLASGSADGTVRLWDLATGELLRT 283

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 3167 LRGHRAPVSALCInelTGD----IVSCAGTYIHVWSINGNPIVSvnTFTGRSQQIVCCCVSEMNEWdtqnvIVTGHSDGV 3242
Cdd:COG2319    284 LTGHSGGVNSVAF---SPDgkllASGSDDGTVRLWDLATGKLLR--TLTGHTGAVRSVAFSPDGKT-----LASGSDDGT 353

                          170
                   ....*....|....
gi 1910339379 3243 VRFWRMEFLQVPET 3256
Cdd:COG2319    354 VRLWDLATGELLRT 367

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 1910339379 3087 AICPNPKLVITGGTSTVVCVWEM--GTSKEKAKTLTLKQA--------------LLGHTDTVTCATASLAYHIIVSGSRD 3150
Cdd:pfam20426  131 AVTSDGSILATGSYDTTVMVWEVlrGRSSEKRSRNTQTEFprkdhviaetpfhiLCGHDDIITCLYVSVELDIVISGSKD 210

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1910339379 3151 RTCIIWDLNKLSFLTQLRG-HRAPVSALCINElTGDIVSCAGT--YIHVWSINGNPIVSVNTfTGR--SQQIVCC 3220
Cdd:pfam20426  211 GTCIFHTLREGRYVRSIRHpSGCPLSKLVASR-HGRIVLYADDdlSLHLYSINGKHIASSES-NGRlnCIELSSC 283

Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2698 QRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRFKDWE 2777
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2778 DPNgetPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASkHNMADVKELIPEFFYLPE 2857
Cdd:pfam02138   81 DDD---PPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2858 FLFNSNNFDLGCKQNGTKLGDVILPPWAKGDPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHLF 2937
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 1910339379 2938 YEGQVDIYNINDPLKETATIGFINNFGQIPKQLFKKPHPPK 2978
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 1910339379 2697 TQRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRFkdW 2776
Cdd:cd06071      1 TKKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPIFPWVISDYTSEELDLNDPSTYRDLSKPIGALNKERLQLLKERY--E 78

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2777 EDPNGETPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASKhNMADVKELIPEFFYLP 2856
Cdd:cd06071     79 SDSDDSDPPFHYGSHYSNPAIVLYYLVRLEPFTTLHLSLQGGHFDAADRLFNSIPSSWRSASE-NPSDVKELIPEFYYLP 157

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 2857 EFLFNSNNFDLGcKQNGTKLGDVILPPWAKGdPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHL 2936
Cdd:cd06071    158 EFFLNINKFDFG-KQDGEKVNDVELPPWAKS-PEEFIRKHREALESEYVSKNLHHWIDLIFGYKQRGEEAVKAKNVFHPL 235

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|..
gi 1910339379 2937 FYEGQVDIYNINdpLKETATIGFINNFGQIPKQLFKKPHPPK 2978
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 1910339379 2536 EKIQHMYRCARVQGLDTSEGLLLFGKEHFYVIDGFTMTATREIRDIETlppnmhepiiprgaRQGPSQLKRTCSSFAYED 2615
Cdd:cd01201      1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVINS--------------QKVLSYKEHLVFKWSLSD 66

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....
gi 1910339379 2616 IKEVHKRRYLLQPIAVEVFSGDGRNYLLAFQKGIRNKVYQRFLA 2659
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 1910339379 3452 DHWVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSE-IKRLKISSPVRVCQNCYYNLQH 3518
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 1910339379 3049 NKTFAWSYADLSCRLGTYESDKAVTVYECLSEWGQiLCAICPNPKLVITGGTSTVVCVWEMGTSKekaktltLKQALLGH 3128
Cdd:cd00200    105 GRILSSSSRDKTIKVWDVETGKCLTTLRGHTDWVN-SVAFSPDGTFVASSSQDGTIKLWDLRTGK-------CVATLTGH 176

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 3129 TDTVTCATASLAYHIIVSGSRDRTCIIWDLNKLSFLTQLRGHRAPVSALCINELTGDIVSCA--GTyIHVWsiNGNPIVS 3206
Cdd:cd00200    177 TGEVNSVAFSPDGEKLLSSSSDGTIKLWDLSTGKCLGTLRGHENGVNSVAFSPDGYLLASGSedGT-IRVW--DLRTGEC 253

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|.
gi 1910339379 3207 VNTFTGRSQQIVCCCVSemnewDTQNVIVTGHSDGVVRFWR 3247
Cdd:cd00200    254 VQTLSGHTNSVTSLAWS-----PDGKRLASGSADGTIRIWD 289

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 1910339379 3082 GQILC-AICPNPKLVITGGTSTVVCVWEMgtskekaKTLTLKQALLGHTDTVTCATASLAYHIIVSGSRDRTCIIWDLNK 3160
Cdd:cd00200     10 GGVTCvAFSPDGKLLATGSGDGTIKVWDL-------ETGELLRTLKGHTGPVRDVAASADGTYLASGSSDKTIRLWDLET 82

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 3161 LSFLTQLRGHRAPVSALCINElTGDIVSCAG---TyIHVWSINGNPIVSvnTFTGRSQQIVCCCVSEmnewdTQNVIVTG 3237
Cdd:cd00200     83 GECVRTLTGHTSYVSSVAFSP-DGRILSSSSrdkT-IKVWDVETGKCLT--TLRGHTDWVNSVAFSP-----DGTFVASS 153

                          170
                   ....*....|..
gi 1910339379 3238 HSDGVVRFWRME 3249
Cdd:cd00200    154 SQDGTIKLWDLR 165

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.

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gi 1910339379 3454 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKisSPVRVCQNCY 3513
Cdd:cd15730      3 WADDEEVQNCMACGKGFSVTVRKHHCRQCGNIFCNECSSKTATTPSSK--KPVRVCDACF 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.

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gi 1910339379 3462 SCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3513
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.

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gi 1910339379 3454 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3513
Cdd:cd15727      4 WVPDKECPVCMSCKKKFDFFKRRHHCRRCGKCFCSDCCSNKVPLPRMCFVDPVRVCNECA 63

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 1910339379 3454 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3513
Cdd:cd15733      1 WVPDHAASHCFGCDCEFWLAKRKHHCRNCGNVFCADCSNYKLPIPDEQLYDPVRVCNSCY 60

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.

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gi 1910339379 3460 GDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3513
Cdd:cd15735      6 SDVCMRCRTAFTFTNRKHHCRNCGGVFCQQCSSKSLPLPHFGINQPVRVCDGCY 59

FYVE domain found in RUN and FYVE domain-containing protein 1 (RUFY1) and similar proteins; 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. RUFY1 contains an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between.

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gi 1910339379 3454 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSrfQSEIKRLKISSPVRVCQNCY 3513
Cdd:cd15758      6 WLKDDEATHCKQCEKEFSISRRKHHCRNCGHIFCNTCS--SNELALPSYPKPVRVCDSCH 63

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.

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gi 1910339379 3454 WVKDEGGDSCSGCS-VRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKiSSPVRVCQNCYYNL 3516
Cdd:cd15754      2 WIPDKATDICMRCTqTNFSLLTRRHHCRKCGFVVCHECSRQRFLIPRLS-PKPVRVCSLCYRKL 64

WD40 repeat [General function prediction only];

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 3087 AICPNPKLVITGGTSTVVCVWEMGTSKEkAKTLTlkqallGHTDTVTcataSLAY----HIIVSGSRDRTCIIWDLNKLS 3162
Cdd:COG2319    127 AFSPDGKTLASGSADGTVRLWDLATGKL-LRTLT------GHSGAVT----SVAFspdgKLLASGSDDGTVRLWDLATGK 195

                           90       100       110       120       130       140       150       160
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gi 1910339379 3163 FLTQLRGHRAPVSALCINElTGDIVSCAGT--YIHVWSINGNPIVSvnTFTGRSQQIVCCCVSEmnewDTQnVIVTGHSD 3240
Cdd:COG2319    196 LLRTLTGHTGAVRSVAFSP-DGKLLASGSAdgTVRLWDLATGKLLR--TLTGHSGSVRSVAFSP----DGR-LLASGSAD 267

                   ....*..
gi 1910339379 3241 GVVRFWR 3247
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.

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gi 1910339379 3453 HWVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3513
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.

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gi 1910339379 3454 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3513
Cdd:cd15732      2 WVPDHLAASCYGCEREFWLASRKHHCRNCGNVFCGSCCNQKLPVPSQQLFEPSRVCKSCF 61

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.

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gi 1910339379 3454 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3513
Cdd:cd15734      2 WVPDSEIKECSVCKRPFSPRLSKHHCRACGQGVCDDCSKNRRPVPSRGWDHPVRVCDPCA 61

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 1910339379 3454 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKiSSPVRVCQNCY 3513
Cdd:cd15743      3 WIPDSRVTMCMICTSEFTVTWRRHHCRACGKVVCGSCSSNKAPLEYLK-NKSARVCDECF 61

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

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                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910339379 3454 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSrfQSEIKRLKISSPVRVCQNCY 3513
Cdd:cd15759      4 WLKDKEATHCKLCEKEFSLSKRKHHCRNCGEIFCNACS--DNELPLPSSPKPVRVCDSCH 61

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 1910339379 3463 CSGCSVRFSLTERRHHCRNCGQLFCQK-CSR---FQSEIKRLKISSPVRVCQNCY 3513
Cdd:cd15736      2 CHTCSRTFNLNIRAHHCRKCGKLFCRRhLPNmipLNLSAYDPRNGKWYRCCHSCF 56