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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 201066253 665 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNaqgqPGKPVRVCDNCY 726
Cdd:cd15721    1 WADDKEVTHCQQCEKEFSLSRRKHHCRNCGGIFCNSCSDNTMPLPS----SAKPVRVCDTCY 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 201066253  168 HFFIVIEHVLGHGLRP------KKGLLGPRKELWDLLQSVEHYCPEAQDITASVRDLPTVRT---HIGRARAWLRIALMQ 238
Cdd:pfam02759   1 QLCAALEALLSHGLKRssllilRAAGLLPERSFWALLERVGKLVPPAEELLSSVQELEQIHTpysPDGRGRAWIRLALNE 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 201066253  239 KKLSDYLQALIEHREdSLFDYYEPHALMMSDEIV-VIMGILVGLNVIDCNLCVK 291
Cdd:pfam02759  81 KLLDQWLKLLLSNKE-LLSEYYEPWALLADPEFGeILLGLLVGLSALDFNLCLK 133

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 201066253  665 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNAQGQpGKPVRVCDNCYAA 728
Cdd:pfam01363   3 WVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISLLPELGS-NKPVRVCDACYDT 65

domain involved in Ras-like GTPase signaling;

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 201066253   228 ARAWLRIALMQKKLSDYLQALIEHREdSLFDYYEPHALMMSDE-IVVIMGILVGLNVIDCNLCVK 291
Cdd:smart00593   1 FRAWIRLALNEKLLSSWLNLLLSDEE-LLSKYYEPWAFLRDPEeGEQLLGLLVGLSALDFNLPVD 64

chromosome segregation protein SMC, common bacterial 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. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 201066253   408 GSGGSSDKDKEKASEELVEERRKNSELEKELKLQVSLKAESDMAMKLLEKDIHEKQDTIVSLRRQLDDIKQINLEMYRKL 487
Cdd:TIGR02168  656 RPGGVITGGSAKTNSSILERRREIEELEEKIEELEEKIAELEKALAELRKELEELEEELEQLRKELEELSRQISALRKDL 735

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 201066253   488 QDCKASLTHKTELMTKLEVQKEDMASTIDQLEKKWSHDKSNLGEiLKTTSQTLTTQVTASEERAARAEAESRIER----E 563
Cdd:TIGR02168  736 ARLEAEVEQLEERIAQLSKELTELEAEIEELEERLEEAEEELAE-AEAEIEELEAQIEQLKEELKALREALDELRaeltL 814

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 201066253   564 WRISLQEKELKLKEKIANLQGCLKELSEEKERNGKLKADLDKVRTQWSEAQTTLEELGIQLSvsklKVSEMQDQERRQRQ 643
Cdd:TIGR02168  815 LNEEAANLRERLESLERRIAATERRLEDLEEQIEELSEDIESLAAEIEELEELIEELESELE----ALLNERASLEEALA 890

                          250
                   ....*....|.
gi 201066253   644 LLSGSAQSLQA 654
Cdd:TIGR02168  891 LLRSELEELSE 901

DNA double-strand break repair ATPase Rad50;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 201066253 413 SDKDKEKASEELVEERRKNSELEKELKLQVSLKAEsdmamklLEKDIHEKQDTIVSLRrqlddikqinlEMYRKLQDCKA 492
Cdd:PRK03918 382 TGLTPEKLEKELEELEKAKEEIEEEISKITARIGE-------LKKEIKELKKAIEELK-----------KAKGKCPVCGR 443

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 201066253 493 SLT--HKTELMTKLEVQKEDMASTIDQLEKKWSHDKSNLGEILKTTSQ--TLTTQVTASEERAARAEAESRI-----ERE 563
Cdd:PRK03918 444 ELTeeHRKELLEEYTAELKRIEKELKEIEEKERKLRKELRELEKVLKKesELIKLKELAEQLKELEEKLKKYnleelEKK 523

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 201066253 564 WRI--SLQEKELKLKEKIANLQGCLKELSEEKERNGKLKADLDKVRTQWSEAQTTLEELG 621
Cdd:PRK03918 524 AEEyeKLKEKLIKLKGEIKSLKKELEKLEELKKKLAELEKKLDELEEELAELLKELEELG 583

RUN domain found in RUN and FYVE domain-containing protein 2 (RUFY2) and similar proteins; RUFY2, also called 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. This model represents the RUN domain of RUFY2.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 201066253 133 ERSNLVNICKLVVKELLEQSLRYGRMLDSDHLPLQHFFIVIEHVLGHGLRPKKGLLGPRKELWDLLQSVEHYCPEAQDIT 212
Cdd:cd17695    1 ERANLLNMAKLSIKGLIESALSFGRTLDSDYPPLQQFFVVMEHCLKHGLKVRKSFLSYNKTIWGPLELVEKLCPEAEEIA 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 201066253 213 ASVRDLPTVRTHIGRARAWLRIALMQKKLSDYLQALIEhREDSLFDYYEPHALMMSDEIVVIMGILVGLNVIDCNLC 289
Cdd:cd17695   81 ASVRDLPGLKTPLGRARAWLRLALMQKKLADYLRCLII-RRDLLSEFYEYHALMMEEEGAVIVGLLVGLNVIDANLC 156

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 201066253 133 ERSNLVNICKLVVKELLEQSLRYGRMLDSDHLPLQHFFIVIEHVLGHGLRPKKGLLGPRKELWDLLQSVEHYCPEAQDIT 212
Cdd:cd17696    1 ERMNLMNMAKLSIKGLIESALNLGRTLDSDYAPLQQFFVVMEHCLKHGLKAKKTFLGQNKSFWGPLELVEKLVPEAAEIT 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 201066253 213 ASVRDLPTVRTHIGRARAWLRIALMQKKLSDYLQALIeHREDSLFDYYEPHALMMSDEIVVIMGILVGLNVIDCNLC 289
Cdd:cd17696   81 ASVKDLPGLKTPVGRGRAWLRLALMQKKLSEYMKALI-NRKDLLSEFYEPNALMMEEEGAIIAGLLVGLNVIDANFC 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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 201066253 665 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNaqgqPGKPVRVCDNCY 726
Cdd:cd15721    1 WADDKEVTHCQQCEKEFSLSRRKHHCRNCGGIFCNSCSDNTMPLPS----SAKPVRVCDTCY 58

Protein present in Fab1, YOTB, Vac1, and EEA1; The FYVE zinc finger is named after four proteins where it was first found: Fab1, YOTB/ZK632.12, Vac1, and EEA1. The FYVE finger has been shown to bind two Zn2+ ions. The FYVE finger has eight potential zinc coordinating cysteine positions. The FYVE finger is structurally related to the PHD finger and the RING finger. Many members of this family also include two histidines in a motif R+HHC+XCG, where + represents a charged residue and X any residue. The FYVE finger functions in the membrane recruitment of cytosolic proteins by binding to phosphatidylinositol 3-phosphate (PI3P), which is prominent on endosomes. The R+HHC+XCG motif is critical for PI3P binding.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 201066253   665 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLlnAQGQPGKPVRVCDNCYA 727
Cdd:smart00064   4 WIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPL--PKLGIERPVRVCDDCYE 64

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 201066253 136 NLVNICKLVVKELLEQSLRYgrMLDSDHLPLQHFFIVIEHVLGHGLRPKKGLLG--PRKELWDLLQSVEHYCPeaQDITA 213
Cdd:cd17684    1 NLVTVCRLSVKSLIDKACLE--TIDDSSEELINFAAILEQILSHRLKPVKPWYGseEPRTFWDYIRVACKKVP--QNCIA 76

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 201066253 214 SVRDLPTVRTHIGRARAWLRIALMQKKLSDYL-QALIEHRedSLFDYYEPHALMMSDEIVVIMGILVGLNVIDCNL 288
Cdd:cd17684   77 SIEQMENIKSPKAKGRAWIRVALMEKRLSEYLsTALKQTR--LTRNFYQDGAIMLSEDATVLCGMLIGLNAIDFSF 150

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 201066253 665 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNAQgqpgKPVRVCDNCY 726
Cdd:cd15730    3 WADDEEVQNCMACGKGFSVTVRKHHCRQCGNIFCNECSSKTATTPSSK----KPVRVCDACF 60

FYVE domain found in Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and similar proteins; scVps27p, also termed Golgi retention defective protein 11, is the putative yeast counterpart of the mammalian protein Hrs and is involved in endosome maturation. It is a mono-ubiquitin-binding protein that interacts with ubiquitinated cargoes, such as Hse1p, and is required for protein sorting into the multivesicular body. Vps27p forms a complex with Hse1p. The complex binds ubiquitin and mediates endosomal protein sorting. At the endosome, Vps27p and a trimeric protein complex, ESCRT-1, bind ubiquitin and are important for multivesicular body (MVB) sorting. Vps27p contains an N-terminal VHS (Vps27/Hrs/STAM) domain, a FYVE domain that binds PtdIns3P, followed by two ubiquitin-interacting motifs (UIMs), and a C-terminal clathrin-binding motif.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 201066253 665 WAPDsiaTHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPlLNAQGQPGKPVRVCDNCY 726
Cdd:cd15760    2 WKPD---SRCDVCRKKFGLFKRRHHCRNCGDSFCSEHSSRRIP-LPHLGPLGVPQRVCDRCF 59

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 201066253 673 HCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNAqgQPGKPVRVCDNCY 726
Cdd:cd00065    1 RCMLCGKKFSLFRRRHHCRRCGRVFCSKCSSKKLPLPSF--GSGKPVRVCDSCY 52

FYVE domains found in zinc finger FYVE domain-containing protein 1 (ZFYV1) and similar proteins; ZFYV1, also termed double FYVE-containing protein 1 (DFCP1), or SR3, or tandem FYVE fingers-1, is a novel tandem FYVE domain containing protein that binds phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) with high specificity over other phosphoinositides. The subcellular distribution of exogenously-expressed ZFYV1 to Golgi, endoplasmic reticulum (ER) and vesicular is governed in part by its FYVE domains but unaffected by wortmannin, a PI3-kinase inhibitor. In addition to C-terminal tandem FYVE domain, ZFYV1 contains an N-terminal putative C2H2 type zinc finger and a possible nucleotide binding P-loop.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 201066253 665 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPlLNAQGQPGkPVRVCDNCY 726
Cdd:cd15734    2 WVPDSEIKECSVCKRPFSPRLSKHHCRACGQGVCDDCSKNRRP-VPSRGWDH-PVRVCDPCA 61

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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 201066253 665 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNAQgqpgKPVRVCDNCY 726
Cdd:cd15758    6 WLKDDEATHCKQCEKEFSISRRKHHCRNCGHIFCNTCSSNELALPSYP----KPVRVCDSCH 63

RUN domain found in RUN domain-containing protein 3A (RUNDC3A) and similar proteins; RUN domain-containing protein 3A (RUNDC3A), also called Rap2-interacting protein 8 (RPIP8), may act as an effector of Rap2A GTPase in neuronal cells. It contains a RUN domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 201066253 136 NLVNICKLVVKELLEQSLryGRMLDSDHLPLQHFFIVIEHVLGHGLRPKKGLLGP--RKELWDLLQSVEHYCPeaQDITA 213
Cdd:cd17699    1 NLITVCRFSVKTLLEKYT--AEPIDDSSEEFVNFAAILEQILSHRFKGPVSWFSSdgQRGFWDYIRLACSKVP--NNCIS 76

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 201066253 214 SVRDLPTVRTHIGRARAWLRIALMQKKLSDYLQ-ALIEHREDSLFdyYEPHALMMSDEIVVIMGILVGLNVIDCNLC 289
Cdd:cd17699   77 SIENMENISTSRAKGRAWIRVALMEKRLSEYIAtALRDTRTTRRF--YDDGAIMLREESTVLTGMLIGLSAIDFSFC 151

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 201066253 665 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACS--EHTLPLLNAQgqpgKPVRVCDNCYAA 728
Cdd:cd15719    3 WVKDEGGDSCTGCSVRFSLTERRHHCRNCGQLFCSKCSrfESEIRRLRIS----RPVRVCQACYNI 64

RUN domain found in RUN and FYVE domain-containing protein 4 (RUFY4), FYVE and coiled-coil domain-containing protein 1 (FYCO1), and similar proteins; The family includes RUFY4 and FYCO1. RUFY4 acts as a positive regulator that enhances autophagy and lysosome tethering in response to Interleukin-4. It is expressed in a cell-specific manner or under specific immunological conditions associated with IL4 expression such as allergic asthma. FYCO1, also called zinc finger FYVE domain-containing protein 7 (ZFYVE7), is a multidomain autophagy adaptor protein that interacts with kinesin motor proteins and with the autophagosomal membrane components microtubule-associated protein 1 light chain 3 (LC3), Rab7, and phosphatidylinositol 3-phosphate (PI3P), to mediate microtubule plus-end-directed autophagosome transport. Both RUFY4 and FYCO1 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 201066253 160 DSDHLPLQHFFIVIEHVLGHGLRPKKGLLGPRKELWDLLQSVEHYCPEA----QDITASVRDLPTVRTHIGRARAWLRIA 235
Cdd:cd17682   18 DPDNPYLRPFCETLEKILRKGLKEKVSLGGRRKDYWDWLEELLKKLNKIpkslSDAVKFVKSCKKVKTNQGRGRLFIRYA 97

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 201066253 236 LMQKKLSDYLQALIEHReDSLFDYYEPHALmMSDEI 271
Cdd:cd17682   98 LNKKCLHDPVQQLVKNP-KLLSDYYSPDSI-LGNEI 131

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 201066253 664 IWAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEH--TLPLLNaqgqpGKPVRVCDNCYAA 728
Cdd:cd15729    6 VWVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLkaRLEYLD-----NKEARVCVPCYQT 67

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.

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gi 201066253 674 CTACEREFNLTRRKHHCRSCGEIFCKACS--EHTLPLLNAQgqpgKPVRVCDNCY 726
Cdd:cd15720    8 CHRCRVQFGVFQRKHHCRACGQVFCGKCSskSSTIPKFGIE----KEVRVCDPCY 58

FYVE domain found in protein containing both PH and FYVE domains 2 (phafin-2) and similar proteins; Phafin-2, also termed endoplasmic reticulum-associated apoptosis-involved protein containing PH and FYVE domains (EAPF), or pleckstrin homology domain-containing family F member 2 (PKHF2), or PH domain-containing family F member 2, or PH and FYVE domain-containing protein 2, or zinc finger FYVE domain-containing protein 18, is a ubiquitously expressed endoplasmic reticulum-associated protein that facilitates tumor necrosis factor alpha (TNF-alpha)-triggered cellular apoptosis through endoplasmic reticulum (ER)-mitochondrial apoptotic pathway. It is an endosomal phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) effector, as well as an interactor of the endosomal-tethering protein EEA1. It regulates endosome fusion upstream of Rab5. Phafin-2 also functions as a novel regulator of endocytic epidermal growth factor receptor (EGFR) degradation through a role in endosomal fusion.

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gi 201066253 664 IWAPDSIATHCTACER-EFNLTRRKHHCRSCGEIFCKACSEHTLPLlnaQGQPGKPVRVCDNCY 726
Cdd:cd15755    1 VWVPDSEATVCMRCQKaKFTPVNRRHHCRKCGFVVCGPCSEKKFLL---PSQSSKPVRVCDFCY 61

FYVE domain found in FYVE and coiled-coil domain-containing protein 1 (FYCO1) and similar proteins; FYCO1, also termed zinc finger FYVE domain-containing protein 7, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding protein that is associated with the exterior of autophagosomes and mediates microtubule plus-end-directed vesicle transport. It acts as an effector of GTP-bound Rab7, a GTPase that recruits FYCO1 to autophagosomes and has been implicated in autophagosome-lysosomal fusion. FYCO1 also interacts with two microtubule motor proteins, kinesin (KIF) 5B and KIF23, and thus functions as a platform for assembly of vesicle fusion and trafficking factors. FYCO1 contains an N-terminal alpha-helical RUN domain followed by a long central coiled-coil region, a FYVE domain and a GOLD (Golgi dynamics) domain in C-terminus.

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gi 201066253 665 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTlpLLNAQGqpGKPVRVCDNCY 726
Cdd:cd15726    1 WQDDTDVTHCLDCKSEFSWMVRRHHCRLCGRIFCYACSNFY--VLTAHG--GKKERCCKACF 58

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 201066253 665 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPllnaQGQPGKPVRVCDNCY 726
Cdd:cd15739    4 WQHEDDVDQCPNCKTPFSVGKRKHHCRHCGKIFCSDCLTKTVP----SGPNRRPARVCDVCH 61

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

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gi 201066253 665 WAPDSIATHCTAcerEFNLTRRKHHCRSCGEIFCKACSEHTLPLLnaQGQPGKPVRVCDNCY 726
Cdd:cd15728    4 WADGDYCYECGV---KFGITTRKHHCRHCGRLLCSKCSTKEVPII--KFDLNKPVRVCDVCF 60

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 201066253 674 CTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNAQGQP--GKPVRVCDNCY 726
Cdd:cd15736    2 CHTCSRTFNLNIRAHHCRKCGKLFCRRHLPNMIPLNLSAYDPrnGKWYRCCHSCF 56

FYVE domain found in FYVE, RhoGEF and PH domain-containing protein facio-genital dysplasia FGD1, FGD2, FGD4; This family represents a group of Rho GTPase cell division cycle 42 (Cdc42)-specific guanine nucleotide exchange factors (GEFs), including FYVE, RhoGEF and PH domain-containing protein FGD1, FGD2 and FGD4. FGD1, also termed faciogenital dysplasia 1 protein, or Rho/Rac guanine nucleotide exchange factor FGD1 (Rho/Rac GEF), or zinc finger FYVE domain-containing protein 3, is a central regulator of extracellular matrix remodeling and belongs to the DBL family of GEFs that regulate the activation of the Rho GTPases. FGD1 is encoded by gene FGD1. Disabling mutations in the FGD1 gene cause the human X-linked developmental disorder faciogenital dysplasia (FGDY, also known as Aarskog-Scott syndrome). FGD2, also termed zinc finger FYVE domain-containing protein 4, is expressed in antigen-presenting cells, including B lymphocytes, macrophages, and dendritic cells. It localizes to early endosomes and active membrane ruffles. It plays a role in leukocyte signaling and vesicle trafficking in cells specialized to present antigen in the immune system. FGD4, also termed actin filament-binding protein frabin, or FGD1-related F-actin-binding protein, or zinc finger FYVE domain-containing protein 6, functions as an F-actin-binding (FAB) protein showing significant homology to FGD1. It induces the formation of filopodia through the activation of Cdc42 in fibroblasts. Those FGD proteins possess a similar domain organization that contains a DBL homology (DH) domain, a pleckstrin homology (PH) domain, a FYVE domain, and another PH domain in the C-terminus. However, each FGD has a unique N-terminal region that may directly or indirectly interact with F-actin. FGD1 and FGD4 have an N-terminal proline-rich domain (PRD) and an N-terminal F-actin binding (FAB) domain, respectively. This model corresponds to the 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. FGD1 possesses a FYVE-like domain that lack the N-terminal WxxD motif. Moreover, FGD2 is the only known RhoGEF family member shown to have a functional FYVE domain and endosomal binding activity.

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gi 201066253 665 WAPDSIATHCTACEREFN-LTRRKHHCRSCGEIFCKACSEHTLPLlnaQGQPGKPVRVCDNCYAA 728
Cdd:cd15741    3 WVRDNEVTMCMRCKEPFNaLTRRRHHCRACGYVVCWKCSDYKATL---EYDGNKLNRVCKHCYVI 64

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).

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gi 201066253 674 CTACERE-FNLTRRKHHCRSCGEIFCKACSEHTLPLLNaqgQPGKPVRVCDNCY 726
Cdd:cd15744    2 CSLCQEDfASLALPKHNCYNCGGTFCDACSSNELPLPS---SIYEPARVCDVCY 52

FYVE-related domain found in RUN and FYVE domain-containing protein 4 (RUFY4) and similar proteins; RUFY4 belongs to the FUFY protein family which is characterized by the presence of an N-terminal RUN domain and a C-terminal FYVE domain. The FYVE domain of RUFY4 resembles the FYVE-related domain as it lacks the WxxD motif (x for any residue). The biological function of RUFY4 still remains unclear.

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gi 201066253 673 HCTACEREFNLTRRKHHCRSCGEIFCKACSeHTLPLLNAQGQPGKpVRVCDNCY 726
Cdd:cd15745    1 ACAICAKAFSLFRRKYVCRLCGGVVCHSCS-SEDLVLSVPDTCIY-LRVCKTCY 52

RUN domain found in pleckstrin homology domain-containing family M member 2 (PLEKHM2) and similar proteins; PLEKHM2, also called PH domain-containing family M member 2, or Salmonella-induced filaments A (SifA) and Kinesin-Interacting Protein (SKIP), is the lysosome, melanosome and lytic granule cargo adaptor that controls lysosome positioning using a composite kinesin-1 heavy and light chain-binding domain. In addition to kinesin-1, it also interacts with several Rabs to affect endosomal trafficking. This model represents the RUN domain of PLEKHM2.

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gi 201066253 136 NLVNICKlVVKELLEQSL---RYGRMLDSDHLPLQHFFIVIEHVLGHGLRPkkgllgPRKELWDLLQSVEHycPEAQDit 212
Cdd:cd17680    2 ILRNISE-AIKSLQSYSSsqeEEDVLITNENRELQRLCEALDHALLHGLRR------GNRGYWPFVKEFTH--KETIK-- 70