FYVE domain like superfamily; FYVE domain is a 60-80 residue double zinc finger motif-containing module named after the four proteins, Fab1, YOTB, Vac1, and EEA1. The canonical FYVE domains are distinguished from other zinc fingers by three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif, which form a compact phosphatidylinositol 3-phosphate (PtdIns3P, also termed PI3P)-binding site. They are found in many membrane trafficking regulators, including EEA1, Hrs, Vac1p, Vps27p, and FENS-1, which locate to early endosomes, specifically bind PtdIns3P, and play important roles in vesicular traffic and in signal transduction. Some proteins, such as rabphilin-3A and alpha-Rab3-interacting molecules (RIMs), are also involved in membrane trafficking and bind to members of the Rab subfamily of GTP hydrolases. However, they contain FYVE-related domains that are structurally similar to the canonical FYVE domains but lack the three signature sequences. At this point, they may not bind to phosphoinositides. In addition, this superfamily also contains the third group of proteins, caspase-associated ring proteins CARP1 and CARP2. They do not localize to membranes in the cell and are involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8 and caspase 10, which are distinguished from other FYVE-type proteins. Moreover, these proteins have an altered sequence in the basic ligand binding patch and lack the WxxD motif that is conserved only in phosphoinositide binding FYVE domains. Thus they constitute a family of unique FYVE-type domains called FYVE-like domains. The FYVE domain is structurally similar to the RING domain and the PHD finger. This superfamily also includes ADDz zinc finger domain, which is a PHD-like zinc finger motif that contains two parts, a C2-C2 and a PHD-like zinc finger.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847 534 GLVWLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPSSPKPVRVCDSCHAMLIQRCSS 603
Cdd:cd15759    1 GQVWLKDKEATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPSSPKPVRVCDSCHAMLIQRCSS 70

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847 534 GLVWLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPSSPKPVRVCDSCHAMLIQRCSS 603
Cdd:cd15759    1 GQVWLKDKEATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPSSPKPVRVCDSCHAMLIQRCSS 70

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 274318847  536 VWLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLP---SSPKPVRVCDSCHAML 597
Cdd:pfam01363   2 VWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISLLpelGSNKPVRVCDACYDTL 66

domain involved in Ras-like GTPase signaling;

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 274318847   105 ARAWLRLALMQKKMADYLRCLIIQRELLSEFYEYHALMM-EEEGAVIVGLLVGLNVIDANLCVK 167
Cdd:smart00593   1 FRAWIRLALNEKLLSSWLNLLLSDEELLSKYYEPWAFLRdPEEGEQLLGLLVGLSALDFNLPVD 64

chromosome segregation protein SMC, primarily archaeal type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. It is found in a single copy and is homodimeric in prokaryotes, but six paralogs (excluded from this family) are found in eukarotes, where SMC proteins are heterodimeric. This family represents the SMC protein of archaea and a few bacteria (Aquifex, Synechocystis, etc); the SMC of other bacteria is described by TIGR02168. The N- and C-terminal domains of this protein are well conserved, but the central hinge region is skewed in composition and highly divergent. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847   268 RTRQHLEVTKVDVETELQTYKHSRQGLDEMYDDARRQLRDESQLRQDVENELSVQVGMKHEIELAMKLLEKDiHEKQdtl 347
Cdd:TIGR02169  660 RAPRGGILFSRSEPAELQRLRERLEGLKRELSSLQSELRRIENRLDELSQELSDASRKIGEIEKEIEQLEQE-EEKL--- 735

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847   348 iglRQQLEEVKAINIEMYQKLQGSEDGLKEKNEIIARLEEKTNKITTAMRQLEQRLQQAEKAQMEAEDED-EKYAQEC-- 424
Cdd:TIGR02169  736 ---KERLEELEEDLSSLEQEIENVKSELKELEARIEELEEDLHKLEEALNDLEARLSHSRIPEIQAELSKlEEEVSRIea 812

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847   425 --------LSKSDSLQRQISQKEQQLVQLETDLKIEKEWRQTLQEDLQKEKDVLSHLRHETQ-KIISLKKEFLNLQDENQ 495
Cdd:TIGR02169  813 rlreieqkLNRLTLEKEYLEKEIQELQEQRIDLKEQIKSIEKEIENLNGKKEELEEELEELEaALRDLESRLGDLKKERD 892

                          250       260       270
                   ....*....|....*....|....*....|....*....
gi 274318847   496 QLKRIYHEQEQALQELGSKLCESKLKIDDIKEANKALQG 534
Cdd:TIGR02169  893 ELEAQLRELERKIEELEAQIEKKRKRLSELKAKLEALEE 931

Family of unknown function (DUF5401); This is a family of unknown function found in Chromadorea.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847  184 LKNEEEIGNKERNVQIAAILDQKNYVEELNRQLNSTvsSLHSRVDSLEKSNTkliEELAIAKNNIIKLQEENHQLRSENE 263
Cdd:pfam17380 318 LEEAEKARQAEMDRQAAIYAEQERMAMERERELERI--RQEERKRELERIRQ---EEIAMEISRMRELERLQMERQQKNE 392

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847  264 lilmRTRQHLEVTKvdvETELQTYKHSRQgldemyddARRQLRDESQLRQDVENELSVQVG-MKHEIELAMKLLEKDIHE 342
Cdd:pfam17380 393 ----RVRQELEAAR---KVKILEEERQRK--------IQQQKVEMEQIRAEQEEARQREVRrLEEERAREMERVRLEEQE 457

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847  343 KQDTLIGLRQQLEEVKAINIEMYQKLQGSEDGLKEKNEIIAR-LEEKTNKITTAMRQ---LEQRLQQAEKAQMEAED--- 415
Cdd:pfam17380 458 RQQQVERLRQQEEERKRKKLELEKEKRDRKRAEEQRRKILEKeLEERKQAMIEEERKrklLEKEMEERQKAIYEEERrre 537

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|...
gi 274318847  416 -EDEKYAQECLSKSDSLQRQISQKEQQLVQLETDLKIEKEWRQTLQEDLQKEK 467
Cdd:pfam17380 538 aEEERRKQQEMEERRRIQEQMRKATEERSRLEAMEREREMMRQIVESEKARAE 590

phosphatidylinositol kinase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847  530 KALQGLVWLKDKDAT-HCKLCEKEF-SLSK----RKHHCRNCGEIFCNAC-------SDNELPLPSSPKPVR---VCDSC 593
Cdd:PTZ00303  446 KLLHNPSWQKDDESSdSCPSCGRAFiSLSRplgtRAHHCRSCGIRLCVFCitkrahySFAKLAKPGSSDEAEerlVCDTC 525

                  .
gi 274318847  594 H 594
Cdd:PTZ00303  526 Y 526

RUN domain found in RUN and FYVE domain-containing proteins, RUFY1, RUFY2, RUFY3 and similar proteins; This family includes RUN and FYVE domain-containing protein RUFY1, RUFY2, and RUFY3. RUFY1, also called 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 homolog of mouse Rabip4, an effector of Rab4 GTPase that regulates recycling of endocytosed cargo. RUFY1 is an endosomal protein that functions as a dual effector of Rab4 and Rab14 and is involved in efficient recycling of transferrin (Tfn). It is a downstream effector of Etk, a downstream tyrosine kinase of PI3-kinase that is involved in regulation of vesicle trafficking. RUFY2, also called Rab4-interacting protein related, is a novel embryonic factor that is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions. RUFY3, also called Rap2-interacting protein x (RIPx or RPIPx), or single axon-regulated protein (singar), is an N-terminal RUN domain and a C-terminal FYVE domain containing protein predominantly expressed in the brain. It suppresses formation of surplus axons for neuronal polarity. Unlike other RUFY proteins, RUFY3 can associate with the GTP-bound active form of Rab5. RUFY1, RUFY2, and RUFY3 contain an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between; this model represents the RUN domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847  10 ERANLLNMAKLSIKGLIESALSFGRTLDSDYPPLQQFFVVMEHCLKHGLKVRKSFLSYNKTIWGPLELVEKLYPEAEEIG 89
Cdd:cd17681    1 ERRNLLNLAKLSIKELIESALSFGRTLDSDHVPLQQFFVILEHVLRHGLKVKKSFLGPNKSFWPVLEHVEKLVPEANEIT 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 274318847  90 ASVRDLPGLKTPLGRARAWLRLALMQKKMADYLRCLIIQRELLSEFYEYHALMMEEEGAVIVGLLVGLNVIDANL 164
Cdd:cd17681   81 ASVRDLPGIKTPLGRARAWLRLALMQKKLADYFRALIENKDLLSEFYEPGALMMSEEAVVIAGLLVGLNVIDCNL 155

RUN domain found in RUN and FYVE domain-containing protein 3 (RUFY3) and similar proteins; RUFY3, also called Rap2-interacting protein x (RIPx or RPIPx), or single axon-regulated protein (singar), is an N-terminal RUN domain and a C-terminal FYVE domain containing protein predominantly expressed in the brain. It suppresses formation of surplus axons for neuronal polarity. Unlike other RUFY proteins, RUFY3 can associate with the GTP-bound active form of Rab5. This model represents the RUN domain of RUFY3.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847  10 ERANLLNMAKLSIKGLIESALSFGRTLDSDYPPLQQFFVVMEHCLKHGLKVRKSFLSYNKTIWGPLELVEKLYPEAEEIG 89
Cdd:cd17696    1 ERMNLMNMAKLSIKGLIESALNLGRTLDSDYAPLQQFFVVMEHCLKHGLKAKKTFLGQNKSFWGPLELVEKLVPEAAEIT 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 274318847  90 ASVRDLPGLKTPLGRARAWLRLALMQKKMADYLRCLIIQRELLSEFYEYHALMMEEEGAVIVGLLVGLNVIDANLC 165
Cdd:cd17696   81 ASVKDLPGLKTPVGRGRAWLRLALMQKKLSEYMKALINRKDLLSEFYEPNALMMEEEGAIIAGLLVGLNVIDANFC 156

FYVE domain found in RUN and FYVE domain-containing protein RUFY1, RUFY2 and similar proteins; This family includes RUN and FYVE domain-containing protein RUFY1 and RUFY2. RUFY1, also termed FYVE-finger protein EIP1, or La-binding protein 1, or Rab4-interacting protein (Rabip4), or Zinc finger FYVE domain-containing protein 12 (ZFY12), a human homologue of mouse Rabip4, an effector of Rab4 GTPase that regulates recycling of endocytosed cargo. RUFY1 is an endosomal protein that functions as a dual effector of Rab4 and Rab14 and is involved in efficient recycling of transferrin (Tfn). It is a downstream effector of Etk, a downstream tyrosine kinase of PI3-kinase that is involved in regulation of vesicle trafficking. RUFY2, also termed Rab4-interacting protein related, is a novel embryonic factor that is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions. Both RUFY1 and RUFY2 contain an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 274318847 537 WLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPSSPKPVRVCDSCH 594
Cdd:cd15721    1 WADDKEVTHCQQCEKEFSLSRRKHHCRNCGGIFCNSCSDNTMPLPSSAKPVRVCDTCY 58

RUN domain; This domain is present in several proteins that are linked to the functions of GTPases in the Rap and Rab families. They could hence play important roles in multiple Ras-like GTPase signalling pathways. The domain is comprises six conserved regions, which in some proteins have considerable insertions between them. The domain core is thought to take up a predominantly alpha fold, with basic amino acids in regions A and D possibly playing a functional role in interactions with Ras GTPases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847   45 QFFVVMEHCLKHGLKV------RKSFLSYNKTIWGPLELVEKLYPEAEEIGASVRDLPGLKT---PLGRARAWLRLALMQ 115
Cdd:pfam02759   1 QLCAALEALLSHGLKRssllilRAAGLLPERSFWALLERVGKLVPPAEELLSSVQELEQIHTpysPDGRGRAWIRLALNE 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 274318847  116 KKMADYLRCLIIQRELLSEFYEYHALMMEEEGA-VIVGLLVGLNVIDANLCVKG 168
Cdd:pfam02759  81 KLLDQWLKLLLSNKELLSEYYEPWALLADPEFGeILLGLLVGLSALDFNLCLKL 134

RUN domain found in RUN domain-containing protein 3 (RUNDC3) and similar proteins; RUNDC3 contains two isoforms, RUNDC3A and RUNDC3B. RUNDC3A, also called Rap2-interacting protein 8 (RPIP8), may act as an effector of Rap2A GTPase in neuronal cells. RUNDC3B, also called Rap2-binding protein 9, or Rap2-interacting protein 9 (RPIP-9), contains a RUN domain in its N-terminal region that mediates interaction with Rap2, an important component of the Mitogen-Activated Protein Kinase (MAPK) cascade, which regulates cellular proliferation and differentiation. It also contains characteristic binding sites for MAPK intermediates. Both RUNDC3A and RUNDC3B contain a RUN domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847  13 NLLNMAKLSIKGLIESALSfgRTLDSDYPPLQQFFVVMEHCLKHGLKVRKSFLSY--NKTIWGPLELVEKLYPEaeEIGA 90
Cdd:cd17684    1 NLVTVCRLSVKSLIDKACL--ETIDDSSEELINFAAILEQILSHRLKPVKPWYGSeePRTFWDYIRVACKKVPQ--NCIA 76

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 274318847  91 SVRDLPGLKTPLGRARAWLRLALMQKKMADYLRCLIIQRELLSEFYEYHALMMEEEGAVIVGLLVGLNVIDANL 164
Cdd:cd17684   77 SIEQMENIKSPKAKGRAWIRVALMEKRLSEYLSTALKQTRLTRNFYQDGAIMLSEDATVLCGMLIGLNAIDFSF 150

RUN domain; RUN domain, named after RPIP8 (Rap2 interacting protein 8), UNC-14 and NESCA (new molecule containing SH3 at the carboxyl-terminus), is a less conserved protein motif that comprises six conserved regions, which in some proteins have considerable insertions between them. The domain core is thought to take up a predominantly alpha fold, with basic amino acids in regions A and D possibly playing a functional role in interactions with Ras GTPases. RUN domains are often found in proteins linked particularly to the functions of GTPases in the Rap and Rab families, suggesting the RUN domain may be involved in Rab-mediated membrane trafficking, possibly as a Rab-binding site. RUN domain-containing proteins could hence play important roles in multiple Ras-like GTPase signalling pathways.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847  21 SIKGLIESAL-------SFGRTLDSDYPPLQQFFVVMEHCLKHGLKvRKSFLSYNKTIWGPLELVEKLYPEAEEIGA--S 91
Cdd:cd17671    2 AVKELLESFAdngeaddSAALTLTDDDPVVGRLCAALEAILSHGLK-PKRFGGGKVSFWDFLEALEKLLPAPSLKQAirD 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 274318847  92 VRDLPGLKTPLGRARAWLRLALMQKKMADYLRCLIIQRELLSEFYEYHALMM-EEEGAVIVGLLVGLNVIDANL 164
Cdd:cd17671   81 INSLSNVKTDDGRGRAWIRLALNEKSLESYLAALLSDQSLLRKYYEPWALLRdPEEAELFLSLLVGLSSLDFNL 154

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 274318847 533 QGLVWLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPSS--PKPVRVCDSC 593
Cdd:cd15731    1 DPPLWVPDEACPQCMACSAPFTVLRRRHHCRNCGKIFCSRCSSNSVPLPRYgqMKPVRVCNHC 63

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 274318847 536 VWLKDKDATHCKLCEK-EFSLSKRKHHCRNCGEIFCNACSDNELPLPS-SPKPVRVCDSCH 594
Cdd:cd15717    1 VWVPDSEAPVCMHCKKtKFTAINRRHHCRKCGAVVCGACSSKKFLLPHqSSKPLRVCDTCY 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 274318847 537 WLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPSS--PKPVRVCDSC 593
Cdd:cd15734    2 WVPDSEIKECSVCKRPFSPRLSKHHCRACGQGVCDDCSKNRRPVPSRgwDHPVRVCDPC 60

FYVE domain found in WD40 repeat and FYVE domain-containing protein 3 (WDFY3) and similar proteins; WDFY3, also termed autophagy-linked FYVE protein (Alfy), is a ubiquitously expressed phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein required for selective macroautophagic degradation of aggregated proteins. It regulates the protein degradation through the direct interaction with the autophagy protein Atg5. Moreover, WDFY3 acts as a scaffold that bridges its cargo to the macroautophagic machinery via the creation of a greater complex with Atg12, Atg16L, and LC3. It also functionally associates with sequestosome-1/p62 (SQSTM1) in osteoclasts. WDFY3 shuttles between the nucleus and cytoplasm. It predominantly localizes to the nucleus and nuclear membrane under basal conditions, but is recruited to cytoplasmic ubiquitin-positive protein aggregates under stress conditions. WDFY3 contains a PH-BEACH domain assemblage, five WD40 repeats and a PtdIns3P-binding FYVE domain.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 274318847 537 WLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPS--SPKPVRVCDSCHAML 597
Cdd:cd15719    3 WVKDEGGDSCTGCSVRFSLTERRHHCRNCGQLFCSKCSRFESEIRRlrISRPVRVCQACYNIL 65

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 274318847 536 VWLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLP--SSPKPVRVCDSC 593
Cdd:cd15727    3 PWVPDKECPVCMSCKKKFDFFKRRHHCRRCGKCFCSDCCSNKVPLPrmCFVDPVRVCNEC 62

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 274318847 541 KDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPSS--PKPVRVCDSCHAML 597
Cdd:cd15720    3 KDGDECHRCRVQFGVFQRKHHCRACGQVFCGKCSSKSSTIPKFgiEKEVRVCDPCYEKL 61

FYVE-related domain found in RUN and FYVE domain-containing protein 3 (RUFY3) and similar proteins; RUFY3, also termed Rap2-interacting protein x (RIPx or RPIPx), or single axon-regulated protein (singar), is an N-terminal RUN domain and a C-terminal FYVE domain containing protein predominantly expressed in the brain. It suppresses formation of surplus axons for neuronal polarity. Unlike other RUFY proteins, RUFY3 can associate with the GTP-bound active form of Rab5. Moreover, the FYVE domain of RUFY3 resembles the FYVE-related domain as it lacks the WxxD motif (x for any residue).

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 274318847 546 CKLCEKE-FSLSKRKHHCRNCGEIFCNACSDNELPLPSS-PKPVRVCDSCH 594
Cdd:cd15744    2 CSLCQEDfASLALPKHNCYNCGGTFCDACSSNELPLPSSiYEPARVCDVCY 52

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
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 274318847 536 VWLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPS-SPKPVRVCDSC 593
Cdd:cd15743    2 IWIPDSRVTMCMICTSEFTVTWRRHHCRACGKVVCGSCSSNKAPLEYlKNKSARVCDEC 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 274318847 542 DATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLP--SSPKPVRVCDSCH 594
Cdd:cd15735    5 DSDVCMRCRTAFTFTNRKHHCRNCGGVFCQQCSSKSLPLPhfGINQPVRVCDGCY 59

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 274318847 536 VWLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLP-SSPKPVRVCDSCHAML 597
Cdd:cd15729    6 VWVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLEyLDNKEARVCVPCYQTL 68

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 274318847 537 WLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPSSPKP--VRVCDSCH 594
Cdd:cd15725    2 WMPDSSCKECYECSEKFTTFRRRHHCRLCGQIFCSRCCNQEIPGKFIGYPgdLRVCTYCC 61

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 274318847 537 WLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNeLPLpsspkPVRVCDSCHAMLIQR 600
Cdd:cd15716    4 WVNDSDVPFCPDCGKKFNLARRRHHCRLCGSIMCNKCSQF-LPL-----HIRCCHHCKDLLERR 61

FYVE domain found in protein containing both PH and FYVE domains 1 (phafin-1) and similar proteins; Phafin-1, also termed lysosome-associated apoptosis-inducing protein containing PH (pleckstrin homology) and FYVE domains (LAPF), or pleckstrin homology domain-containing family F member 1 (PKHF1), or PH domain-containing family F member 1, or apoptosis-inducing protein, or PH and FYVE domain-containing protein 1, or zinc finger FYVE domain-containing protein 15, is a representative of a novel family of PH and FYVE domain-containing proteins called phafins. It is a ubiquitously expressed pro-apoptotic protein via translocating to lysosomes, facilitating apoptosis induction through a lysosomal-mitochondrial apoptotic pathway.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 274318847 537 WLKDKDATHCKLC-EKEFSLSKRKHHCRNCGEIFCNACSDNELPLPS-SPKPVRVCDSCHAML 597
Cdd:cd15754    2 WIPDKATDICMRCtQTNFSLLTRRHHCRKCGFVVCHECSRQRFLIPRlSPKPVRVCSLCYRKL 64

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 274318847 546 CKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPSSP------KPVRVCDSC 593
Cdd:cd15736    2 CHTCSRTFNLNIRAHHCRKCGKLFCRRHLPNMIPLNLSAydprngKWYRCCHSC 55

FYVE domain 2 found in yeast protein VAC1 (Vac1p) and similar proteins; 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 family corresponds to the second FYVE domain that is responsible for the ability of Pep7p to efficiently interact with Vac1p and Vps45p.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847 537 WLKDKDATHCKLCEKEFSLSKRKHHCRNCGEIFCN----ACS--------------------DNELPLPSSPKPVRVCDS 592
Cdd:cd15737    2 WEDDSSVTHCPICLRSFGLLLRKHHCRLCGKVVCDdrrtKCStevpldllssalpdlpfvfkEPQSDIPDDTKSVRVCRD 81

                 .
gi 274318847 593 C 593
Cdd:cd15737   82 C 82

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 274318847 546 CKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPS-SPKPVRVCDSCHAMLIQR 600
Cdd:cd15742   12 CMNCGSDFTLTLRRHHCHACGKIVCRNCSRNKYPLKYlKDRPAKVCDGCFAELRKR 67

Chromosome segregation ATPase Smc [Cell cycle control, cell division, chromosome partitioning];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847 183 YLKNEEEIGNKERNVQIAAILDQKNYVEELNRQLN---STVSSLHSRVDSLEKSNTKLIEELAIAKNNIIKLQEENHQLR 259
Cdd:COG1196  215 YRELKEELKELEAELLLLKLRELEAELEELEAELEeleAELEELEAELAELEAELEELRLELEELELELEEAQAEEYELL 294

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847 260 SEnELILMRTRQHLEVTKVDVETELQTYKHSRQGLDEMYDDARRQLRDESQLRQDVENELSVQVGMKHEIELAMKLLEKD 339
Cdd:COG1196  295 AE-LARLEQDIARLEERRRELEERLEELEEELAELEEELEELEEELEELEEELEEAEEELEEAEAELAEAEEALLEAEAE 373

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 274318847 340 IHEKQDTLIGLRQQLEEVKAINIEMYQKLQGSEDGLKEKNEIIARLEEKTNKITTAMRQLEQRLQQAEKAQMEAEDEDEK 419
Cdd:COG1196  374 LAEAEEELEELAEELLEALRAAAELAAQLEELEEAEEALLERLERLEEELEELEEALAELEEEEEEEEEALEEAAEEEAE 453

                        250       260       270       280
                 ....*....|....*....|....*....|....*....|....*..
gi 274318847 420 YAQECLSKSDSLQRQisQKEQQLVQLETDLKIEKEWRQTLQEDLQKE 466
Cdd:COG1196  454 LEEEEEALLELLAEL--LEEAALLEAALAELLEELAEAAARLLLLLE 498

FYVE-related domain found in FYVE domain-containing protein 19 (ZFY19) and similar proteins; ZFY19, also termed mixed lineage leukemia (MLL) partner containing FYVE domain, is encoded by a novel gene, MLL partner containing FYVE domain (MPFYVE). The FYVE domain of ZFY19 resembles FYVE-related domains that are structurally similar to the canonical FYVE domains but lack the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif. The biological function of ZFY19 remains unclear.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 274318847 546 CKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPS-SPKPVRVCDSCH 594
Cdd:cd15749    2 CFGCAAKFSLFKKECGCKNCGRSFCKGCLTFSAVVPRkGNQKQKVCKQCH 51