Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226  2679 QRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILSDYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRYKDWE 2758
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226  2759 DPNgetPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASkHNMADVKELIPEFFYLPE 2838
Cdd:pfam02138   81 DDD---PPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226  2839 FLFNSNNFDLGCKQNGTKLGDVILPPWAKGDPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHLF 2918
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 568936226  2919 YEGQVDIYNINDPLKETATIGFINNFGQIPKQLFKKPHPPK 2959
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 568936226 2517 EKIQHMYRCARVQGLDTSEGLLLFGKEHFYVIDGFTMTATREIRDIETlppnmhepiiprgaRQGPSQLKRTCSIFAYED 2596
Cdd:cd01201     1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVINS--------------QKVLSYKEHLVFKWSLSD 66

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 568936226 2597 IKEVHKRRYLLQPIAVEVFSGDGRNYLLAFQKGIRNKVYQRFLA 2640
Cdd:cd01201    67 IREVHKRRYLLRDTALEIFFTDGTNYFLNFPSKERNDVYKKLLS 110

Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226  2679 QRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILSDYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRYKDWE 2758
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226  2759 DPNgetPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASkHNMADVKELIPEFFYLPE 2838
Cdd:pfam02138   81 DDD---PPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226  2839 FLFNSNNFDLGCKQNGTKLGDVILPPWAKGDPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHLF 2918
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 568936226  2919 YEGQVDIYNINDPLKETATIGFINNFGQIPKQLFKKPHPPK 2959
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 568936226 2678 TQRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILSDYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRYkdW 2757
Cdd:cd06071     1 TKKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPIFPWVISDYTSEELDLNDPSTYRDLSKPIGALNKERLQLLKERY--E 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226 2758 EDPNGETPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASKhNMADVKELIPEFFYLP 2837
Cdd:cd06071    79 SDSDDSDPPFHYGSHYSNPAIVLYYLVRLEPFTTLHLSLQGGHFDAADRLFNSIPSSWRSASE-NPSDVKELIPEFYYLP 157

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226 2838 EFLFNSNNFDLGcKQNGTKLGDVILPPWAKGdPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHL 2917
Cdd:cd06071   158 EFFLNINKFDFG-KQDGEKVNDVELPPWAKS-PEEFIRKHREALESEYVSKNLHHWIDLIFGYKQRGEEAVKAKNVFHPL 235

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|..
gi 568936226 2918 FYEGQVDIYNINdpLKETATIGFINNFGQIPKQLFKKPHPPK 2959
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 568936226 2517 EKIQHMYRCARVQGLDTSEGLLLFGKEHFYVIDGFTMTATREIRDIETlppnmhepiiprgaRQGPSQLKRTCSIFAYED 2596
Cdd:cd01201     1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVINS--------------QKVLSYKEHLVFKWSLSD 66

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 568936226 2597 IKEVHKRRYLLQPIAVEVFSGDGRNYLLAFQKGIRNKVYQRFLA 2640
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 568936226  3432 DHWVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSE-IKRLKISSPVRVCQNCYYSLQH 3498
Cdd:pfam01363    1 PVWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISlLPELGSNKPVRVCDACYDTLQK 68

WD40 repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226 3068 AVCPNPKLVITGGTSTVVCVWEMGTSKekakpltLKQALLGHTDTVTcataSLAY----HIIVSGSRDRTCIIWDLNKLS 3143
Cdd:COG2319   169 AFSPDGKLLASGSDDGTVRLWDLATGK-------LLRTLTGHTGAVR----SVAFspdgKLLASGSADGTVRLWDLATGK 237

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226 3144 FLTQLRGHRAPVSALCINeLTGDIVSCAGTY--IHVWSINGNPIVSvnTFTGRSQQIVCCCMSEMNEWdtqnvIVTGHSD 3221
Cdd:COG2319   238 LLRTLTGHSGSVRSVAFS-PDGRLLASGSADgtVRLWDLATGELLR--TLTGHSGGVNSVAFSPDGKL-----LASGSDD 309

                  ....*....
gi 568936226 3222 GVVRFWRME 3230
Cdd:COG2319   310 GTVRLWDLA 318

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 568936226  3068 AVCPNPKLVITGGTSTVVCVWEM--GTSKEKAKPLTLKQA--------------LLGHTDTVTCATASLAYHIIVSGSRD 3131
Cdd:pfam20426  131 AVTSDGSILATGSYDTTVMVWEVlrGRSSEKRSRNTQTEFprkdhviaetpfhiLCGHDDIITCLYVSVELDIVISGSKD 210

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 568936226  3132 RTCIIWDLNKLSFLTQLRG-HRAPVSALCINElTGDIVSCAGT--YIHVWSINGNPIVSVNTfTGR--SQQIVCC 3201
Cdd:pfam20426  211 GTCIFHTLREGRYVRSIRHpSGCPLSKLVASR-HGRIVLYADDdlSLHLYSINGKHIASSES-NGRlnCIELSSC 283

Beige/BEACH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226  2679 QRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILSDYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRYKDWE 2758
Cdd:pfam02138    1 KKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPVFPWVLADYTSEELDLNDPSTYRDLSKPIGALNEERLEKFKERYEELE 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226  2759 DPNgetPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASkHNMADVKELIPEFFYLPE 2838
Cdd:pfam02138   81 DDD---PPFHYGSHYSSPGIVLYYLIRLEPFTTLHIELQGGKFDHPDRLFHSIEEAWRSAS-NSTSDVKELIPEFFYLPE 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226  2839 FLFNSNNFDLGCKQNGTKLGDVILPPWAKGDPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHLF 2918
Cdd:pfam02138  157 FLLNSNNFDLGGRQDGEKVDDVELPPWAKKSPEEFVRKHREALESDYVSENLHEWIDLIFGYKQRGEEAVEALNVFHPLT 236

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|.
gi 568936226  2919 YEGQVDIYNINDPLKETATIGFINNFGQIPKQLFKKPHPPK 2959
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 568936226 2678 TQRWERGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILSDYDSEEVDLTNPKTFRNLAKPMGAQTDERLAQYKKRYkdW 2757
Cdd:cd06071     1 TKKWQNGEISNFEYLMYLNTLAGRSFNDLSQYPIFPWVISDYTSEELDLNDPSTYRDLSKPIGALNKERLQLLKERY--E 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226 2758 EDPNGETPAYHYGTHYSSAMIVASYLVRMEPFTQIFLRLQGGHFDLADRMFHSVREAWYSASKhNMADVKELIPEFFYLP 2837
Cdd:cd06071    79 SDSDDSDPPFHYGSHYSNPAIVLYYLVRLEPFTTLHLSLQGGHFDAADRLFNSIPSSWRSASE-NPSDVKELIPEFYYLP 157

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226 2838 EFLFNSNNFDLGcKQNGTKLGDVILPPWAKGdPREFIRVHREALECDYVSAHLHEWIDLIFGYKQQGPAAVEAVNVFHHL 2917
Cdd:cd06071   158 EFFLNINKFDFG-KQDGEKVNDVELPPWAKS-PEEFIRKHREALESEYVSKNLHHWIDLIFGYKQRGEEAVKAKNVFHPL 235

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|..
gi 568936226 2918 FYEGQVDIYNINdpLKETATIGFINNFGQIPKQLFKKPHPPK 2959
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 568936226 2517 EKIQHMYRCARVQGLDTSEGLLLFGKEHFYVIDGFTMTATREIRDIETlppnmhepiiprgaRQGPSQLKRTCSIFAYED 2596
Cdd:cd01201     1 EKILLSVNCSLVTPLDVIEGRLLITKTHLYFVDDFTISEDGKIVVINS--------------QKVLSYKEHLVFKWSLSD 66

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 568936226 2597 IKEVHKRRYLLQPIAVEVFSGDGRNYLLAFQKGIRNKVYQRFLA 2640
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 568936226  3432 DHWVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSE-IKRLKISSPVRVCQNCYYSLQH 3498
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 568936226 3030 NKTFAWGYADLSCRLGTYESDKAVTVYECLSEWGQiLCAVCPNPKLVITGGTSTVVCVWEMGTSKekakpltLKQALLGH 3109
Cdd:cd00200   105 GRILSSSSRDKTIKVWDVETGKCLTTLRGHTDWVN-SVAFSPDGTFVASSSQDGTIKLWDLRTGK-------CVATLTGH 176

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226 3110 TDTVTCATASLAYHIIVSGSRDRTCIIWDLNKLSFLTQLRGHRAPVSALCINELTGDIVSCA--GTyIHVWsiNGNPIVS 3187
Cdd:cd00200   177 TGEVNSVAFSPDGEKLLSSSSDGTIKLWDLSTGKCLGTLRGHENGVNSVAFSPDGYLLASGSedGT-IRVW--DLRTGEC 253

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|.
gi 568936226 3188 VNTFTGRSQQIVCCCMSemnewDTQNVIVTGHSDGVVRFWR 3228
Cdd:cd00200   254 VQTLSGHTNSVTSLAWS-----PDGKRLASGSADGTIRIWD 289

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 568936226 3434 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3493
Cdd:cd15731     5 WVPDEACPQCMACSAPFTVLRRRHHCRNCGKIFCSRCSSNSVPLPRYGQMKPVRVCNHCF 64

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 568936226 3434 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKisSPVRVCQNCYYSL 3496
Cdd:cd15730     3 WADDEEVQNCMACGKGFSVTVRKHHCRQCGNIFCNECSSKTATTPSSK--KPVRVCDACFDDL 63

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 568936226 3442 SCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3493
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 568936226 3434 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3493
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.

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gi 568936226 3434 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3493
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 568936226 3440 GDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3493
Cdd:cd15735     6 SDVCMRCRTAFTFTNRKHHCRNCGGVFCQQCSSKSLPLPHFGINQPVRVCDGCY 59

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

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gi 568936226 3434 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFqseikrlkISSPVRVCQNCYYSL 3496
Cdd:cd15716     4 WVNDSDVPFCPDCGKKFNLARRRHHCRLCGSIMCNKCSQF--------LPLHIRCCHHCKDLL 58

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 568936226 3434 WVKDEGGDSCSGCS-VRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKiSSPVRVCQNCYYSL 3496
Cdd:cd15754     2 WIPDKATDICMRCTqTNFSLLTRRHHCRKCGFVVCHECSRQRFLIPRLS-PKPVRVCSLCYRKL 64

WD40 repeat [General function prediction only];

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226 3068 AVCPNPKLVITGGTSTVVCVWEMGTSKEKAkplTLKqallGHTDTVTCATASLAYHIIVSGSRDRTCIIWDLNKLSFLTQ 3147
Cdd:COG2319   211 AFSPDGKLLASGSADGTVRLWDLATGKLLR---TLT----GHSGSVRSVAFSPDGRLLASGSADGTVRLWDLATGELLRT 283

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568936226 3148 LRGHRAPVSALCInelTGD----IVSCAGTYIHVWSINGNPIVSvnTFTGRSQQIVCCCMSEMNEWdtqnvIVTGHSDGV 3223
Cdd:COG2319   284 LTGHSGGVNSVAF---SPDgkllASGSDDGTVRLWDLATGKLLR--TLTGHTGAVRSVAFSPDGKT-----LASGSDDGT 353

                         170
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gi 568936226 3224 VRFWRMEFLQVPET 3237
Cdd:COG2319   354 VRLWDLATGELLRT 367

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 568936226 3433 HWVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKISSPVRVCQNCY 3493
Cdd:cd15725     1 YWMPDSSCKECYECSEKFTTFRRRHHCRLCGQIFCSRCCNQEIPGKFIGYPGDLRVCTYCC 61

FYVE domain found in protein containing both PH and FYVE domains 1 (phafin-1), 2 (phafin-2), and similar proteins; This family includes protein containing both PH and FYVE domains 1 (phafin-1) and 2 (phafin-2). Phafin-1 is a representative of a novel family of PH and FYVE domain-containing proteins called phafins. It is a ubiquitously expressed pro-apoptotic protein via translocating to lysosomes, facilitating apoptosis induction through a lysosomal-mitochondrial apoptotic pathway. Phafin-2 is a ubiquitously expressed endoplasmic reticulum-associated protein that facilitates tumor necrosis factor alpha (TNF-alpha)-triggered cellular apoptosis through endoplasmic reticulum (ER)-mitochondrial apoptotic pathway. It is an endosomal phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) effector, as well as an interactor of the endosomal-tethering protein EEA1. It regulates endosome fusion upstream of Rab5. Phafin-2 also functions as a novel regulator of endocytic epidermal growth factor receptor (EGFR) degradation through a role in endosomal fusion.

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gi 568936226 3434 WVKDEGGDSCSGCS-VRFSLTERRHHCRNCGQLFCQKCSRfqseiKRLKI----SSPVRVCQNCY 3493
Cdd:cd15717     2 WVPDSEAPVCMHCKkTKFTAINRRHHCRKCGAVVCGACSS-----KKFLLphqsSKPLRVCDTCY 61

FYVE domain found in FYVE domain-containing protein 26 (ZFY26 or ZFYVE26); ZFY26, also termed FYVE domain-containing centrosomal protein (FYVE-CENT), or spastizin, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein that localizes to the centrosome and midbody. ZFY26 and its interacting partners TTC19 and KIF13A are required for cytokinesis. It also interacts with Beclin 1, a subunit of class III phosphatidylinositol 3-kinase complex, and may have potential implications for carcinogenesis. In addition, it has been considered as the causal agent of a rare form of hereditary spastic paraplegia. ZFY26 contains a FYVE domain that is important for targeting of FYVE-CENT to the midbody.

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gi 568936226 3434 WVKDEGGDSCSGCSV-RFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKiSSPVRVCQNCY 3493
Cdd:cd15724     1 WVPDEAVSVCMVCQVeRFSMFNRRHHCRRCGRVVCSSCSTKKMLVEGYR-ENPVRVCDQCY 60

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.

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                   ....*....|....*....|....*....|....*....|....*....|....
gi 568936226  2585 LKRTCSIFAYEDIKEVHKRRYLLQPIAVEVFSGDGRNYLLAFQ-KGIRNKVYQR 2637
Cdd:pfam14844   44 DKPKHKRWPISDIKEVHLRRYLLRDTALEIFLIDRTSLFFNFPdTGTRRKVYRK 97

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 568936226 3434 WVKDEGGDSCSGCSVRFSLTERRHHCRNCGQLFCQKCSR--FQSEIKRlkisSPVRVCQNCYYSLQHE 3499
Cdd:cd15739     4 WQHEDDVDQCPNCKTPFSVGKRKHHCRHCGKIFCSDCLTktVPSGPNR----RPARVCDVCHTLLVKD 67

FYVE-like domain found in FYVE, RhoGEF and PH domain-containing protein 5 (FGD5) and similar proteins; FGD5, also termed zinc finger FYVE domain-containing protein 23, is an endothelial cell (EC)-specific guanine nucleotide exchange factor (GEF) that regulates endothelial adhesion, survival, and angiogenesis by modulating phosphatidylinositol 3-kinase signaling. It functions as a novel genetic regulator of vascular pruning by activation of endothelial cell-targeted apoptosis. FGD5 is a homologue of FGD1 and contains a DBL homology (DH) domain, a pleckstrin homology (PH) domain, a FYVE domain, and another PH domain in the C-terminus, but lacks the N-terminal proline-rich domain (PRD) found in FGD1. The FYVE domain of FGD5 resembles a FYVE-like domain that is different from the canonical FYVE domains, since it lacks one of the three conserved signature motifs (the WxxD motif) that are involved in phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding and exhibits altered lipid binding specificities.

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                  ....*....|....*....|....*....|....*....|....*....|....*
gi 568936226 3443 CSGCSVRFSLTERRHHCRNCGQLFCQKCSRFQSEIKRLKiSSPVRVCQNCYYSLQ 3497
Cdd:cd15742    12 CMNCGSDFTLTLRRHHCHACGKIVCRNCSRNKYPLKYLK-DRPAKVCDGCFAELR 65