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 599128013 281 ERSNLVNICKLVVKELLEQSLRYGRMLDSDHLPLQHFFIVIEHVLGHGLRPKKGLLGPRKELWDLLQSVEHYCPEAQDIT 360
Cdd:cd17681    1 ERRNLLNLAKLSIKELIESALSFGRTLDSDHVPLQQFFVILEHVLRHGLKVKKSFLGPNKSFWPVLEHVEKLVPEANEIT 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 599128013 361 ASVRDLPTVRTHIGRARAWLRIALMQKKLSDYLQALIEHReDSLFDYYEPHALMMSDEIVVIMGILVGLNVIDCNL 436
Cdd:cd17681   81 ASVRDLPGIKTPLGRARAWLRLALMQKKLADYFRALIENK-DLLSEFYEPGALMMSEEAVVIAGLLVGLNVIDCNL 155

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013 562 DKDKEKASEELVEERRKNSELEKELKLQVSLKAESDMAMKLLEKDIHEKQDTIVSLRRQLDDIKQINLEMYRKLQDCKAS 641
Cdd:COG1196  259 EAELAELEAELEELRLELEELELELEEAQAEEYELLAELARLEQDIARLEERRRELEERLEELEEELAELEEELEELEEE 338

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013 642 LTHKTELMTKLEVQKEDMASTIDQLEKKWSHDKSNLGEILKTTSQTLTTQVTASEERAARAEAESRIEREWRISLQEKEL 721
Cdd:COG1196  339 LEELEEELEEAEEELEEAEAELAEAEEALLEAEAELAEAEEELEELAEELLEALRAAAELAAQLEELEEAEEALLERLER 418

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013 722 KLKEKIANLQgclkELSEEKERNGKLKADLDKVRTQWSEAQTTLEELgIQLSVSKLKVSEMQDQERRQRQLLSGSAQSLQ 801
Cdd:COG1196  419 LEEELEELEE----ALAELEEEEEEEEEALEEAAEEEAELEEEEEAL-LELLAELLEEAALLEAALAELLEELAEAAARL 493

                 ....*.
gi 599128013 802 AMPEAV 807
Cdd:COG1196  494 LLLLEA 499

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 599128013 281 ERSNLVNICKLVVKELLEQSLRYGRMLDSDHLPLQHFFIVIEHVLGHGLRPKKGLLGPRKELWDLLQSVEHYCPEAQDIT 360
Cdd:cd17681    1 ERRNLLNLAKLSIKELIESALSFGRTLDSDHVPLQQFFVILEHVLRHGLKVKKSFLGPNKSFWPVLEHVEKLVPEANEIT 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 599128013 361 ASVRDLPTVRTHIGRARAWLRIALMQKKLSDYLQALIEHReDSLFDYYEPHALMMSDEIVVIMGILVGLNVIDCNL 436
Cdd:cd17681   81 ASVRDLPGIKTPLGRARAWLRLALMQKKLADYFRALIENK-DLLSEFYEPGALMMSEEAVVIAGLLVGLNVIDCNL 155

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 599128013 813 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNaqgqPGKPVRVCDNCY 874
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 599128013   813 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLlnAQGQPGKPVRVCDNCYA 875
Cdd:smart00064   4 WIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPL--PKLGIERPVRVCDDCYE 64

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013 562 DKDKEKASEELVEERRKNSELEKELKLQVSLKAESDMAMKLLEKDIHEKQDTIVSLRRQLDDIKQINLEMYRKLQDCKAS 641
Cdd:COG1196  259 EAELAELEAELEELRLELEELELELEEAQAEEYELLAELARLEQDIARLEERRRELEERLEELEEELAELEEELEELEEE 338

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013 642 LTHKTELMTKLEVQKEDMASTIDQLEKKWSHDKSNLGEILKTTSQTLTTQVTASEERAARAEAESRIEREWRISLQEKEL 721
Cdd:COG1196  339 LEELEEELEEAEEELEEAEAELAEAEEALLEAEAELAEAEEELEELAEELLEALRAAAELAAQLEELEEAEEALLERLER 418

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013 722 KLKEKIANLQgclkELSEEKERNGKLKADLDKVRTQWSEAQTTLEELgIQLSVSKLKVSEMQDQERRQRQLLSGSAQSLQ 801
Cdd:COG1196  419 LEEELEELEE----ALAELEEEEEEEEEALEEAAEEEAELEEEEEAL-LELLAELLEEAALLEAALAELLEELAEAAARL 493

                 ....*.
gi 599128013 802 AMPEAV 807
Cdd:COG1196  494 LLLLEA 499

RecF/RecN/SMC N terminal domain; This domain is found at the N terminus of SMC proteins. The SMC (structural maintenance of chromosomes) superfamily proteins have ATP-binding domains at the N- and C-termini, and two extended coiled-coil domains separated by a hinge in the middle. The eukaryotic SMC proteins form two kind of heterodimers: the SMC1/SMC3 and the SMC2/SMC4 types. These heterodimers constitute an essential part of higher order complexes, which are involved in chromatin and DNA dynamics. This family also includes the RecF and RecN proteins that are involved in DNA metabolism and recombination.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013   556 GSGGS-SDKDKEKASEELVEER-RKNSELEKELKLQVSLKAESDMAMKLLEKDIHEKQDTIVSLRRQLDDIKQINLEMYR 633
Cdd:pfam02463  161 EAAGSrLKRKKKEALKKLIEETeNLAELIIDLEELKLQELKLKEQAKKALEYYQLKEKLELEEEYLLYLDYLKLNEERID 240

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013   634 KLQDCKASLTHKTELMTKLEVQKEDMASTIDQLEKKWSHDKSNLGEILKTTSqtlttqvtaseeraaraeaeSRIEREWR 713
Cdd:pfam02463  241 LLQELLRDEQEEIESSKQEIEKEEEKLAQVLKENKEEEKEKKLQEEELKLLA--------------------KEEEELKS 300

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013   714 ISLQEKELKLKEKianlqgclKELSEEKERNGKLKADLDKVRTQWSEAQTTLEELGIQLSVSKLKVSEMQDQERRQRQLL 793
Cdd:pfam02463  301 ELLKLERRKVDDE--------EKLKESEKEKKKAEKELKKEKEEIEELEKELKELEIKREAEEEEEEELEKLQEKLEQLE 372

                   ....*...
gi 599128013   794 SGSAQSLQ 801
Cdd:pfam02463  373 EELLAKKK 380

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 599128013 281 ERSNLVNICKLVVKELLEQSLRYGRMLDSDHLPLQHFFIVIEHVLGHGLRPKKGLLGPRKELWDLLQSVEHYCPEAQDIT 360
Cdd:cd17681    1 ERRNLLNLAKLSIKELIESALSFGRTLDSDHVPLQQFFVILEHVLRHGLKVKKSFLGPNKSFWPVLEHVEKLVPEANEIT 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 599128013 361 ASVRDLPTVRTHIGRARAWLRIALMQKKLSDYLQALIEHReDSLFDYYEPHALMMSDEIVVIMGILVGLNVIDCNL 436
Cdd:cd17681   81 ASVRDLPGIKTPLGRARAWLRLALMQKKLADYFRALIENK-DLLSEFYEPGALMMSEEAVVIAGLLVGLNVIDCNL 155

RUN domain found in RUN and FYVE domain-containing protein 1 (RUFY1) and similar proteins; 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. RUFY1 contains 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 599128013 281 ERSNLVNICKLVVKELLEQSLRYGRMLDSDHLPLQHFFIVIEHVLGHGLRPKKGLLGPRKELWDLLQSVEHYCPEAQDIT 360
Cdd:cd17694    1 ERANLMNMMKLSIKVLIQSALSLGRTLDSDYPPLQQFFVVLEHCLKHGLKVKKSFIGQNKSFFGPLELVEKLCPEASDIA 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 599128013 361 ASVRDLPTVRTHIGRARAWLRIALMQKKLSDYLQALIEHReDSLFDYYEPHALMMSDEIVVIMGILVGLNVIDCNLC 437
Cdd:cd17694   81 TSARNLPELKTAVGRGRAWLHLALMQKKLADYLKVLIDRK-DLLSEFYEPGALMMEEEGAVIVGLLVGLNVIDANLC 156

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 599128013  316 HFFIVIEHVLGHGLRP------KKGLLGPRKELWDLLQSVEHYCPEAQDITASVRDLPTVRT---HIGRARAWLRIALMQ 386
Cdd:pfam02759   1 QLCAALEALLSHGLKRssllilRAAGLLPERSFWALLERVGKLVPPAEELLSSVQELEQIHTpysPDGRGRAWIRLALNE 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 599128013  387 KKLSDYLQALIEHREdSLFDYYEPHALMMSDEIV-VIMGILVGLNVIDCNLCVK 439
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 599128013  813 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNAQGQpGKPVRVCDNCYAA 876
Cdd:pfam01363   3 WVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISLLPELGS-NKPVRVCDACYDT 65

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 599128013   813 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLlnAQGQPGKPVRVCDNCYA 875
Cdd:smart00064   4 WIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPL--PKLGIERPVRVCDDCYE 64

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 599128013 809 SPGIWAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLlnAQGQPGKPVRVCDNCY 874
Cdd:cd15731    1 DPPLWVPDEACPQCMACSAPFTVLRRRHHCRNCGKIFCSRCSSNSVPL--PRYGQMKPVRVCNHCF 64

FYVE domain found in myotubularin-related protein 4 (MTMR4) and similar proteins; MTMR4, also termed FYVE domain-containing dual specificity protein phosphatase 2 (FYVE-DSP2), or zinc finger FYVE domain-containing protein 11, is an dual specificity protein phosphatase that specifically dephosphorylates phosphatidylinositol 3-phosphate (PtdIns3P or PI3P). It is localizes to early endosomes, as well as to Rab11- and Sec15-positive recycling endosomes, and regulates sorting from early endosomes. Moreover, MTMR4 is preferentially associated with and dephosphorylated the activated regulatory Smad proteins (R-Smads) in cytoplasm to keep transforming growth factor (TGF) beta signaling in homeostasis. It also functions as an essential negative modulator for the homeostasis of bone morphogenetic protein (BMP)/decapentaplegic (Dpp) signaling. In addition, MTMR4 acts as a novel interactor of the ubiquitin ligase Nedd4 (neural-precursor-cell-expressed developmentally down-regulated 4) and may play a role in the biological process of muscle breakdown. MTMR4 contains an N-terminal PH-GRAM (PH-G) domain, a MTM phosphatase domain, a coiled-coil region, and a C-terminal FYVE domain.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 599128013 813 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNAQGQpgKPVRVCDNCY 874
Cdd:cd15733    1 WVPDHAASHCFGCDCEFWLAKRKHHCRNCGNVFCADCSNYKLPIPDEQLY--DPVRVCNSCY 60

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 599128013 821 HCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNAqgQPGKPVRVCDNCY 874
Cdd:cd00065    1 RCMLCGKKFSLFRRRHHCRRCGRVFCSKCSSKKLPLPSF--GSGKPVRVCDSCY 52

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 599128013 813 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNAQGQpgKPVRVCDNCY 874
Cdd:cd15732    2 WVPDHLAASCYGCEREFWLASRKHHCRNCGNVFCGSCCNQKLPVPSQQLF--EPSRVCKSCF 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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 599128013 812 IWAPDSIATHCTACER-EFNLTRRKHHCRSCGEIFCKACSEHTLpLLNAQGQpgKPVRVCDNCY 874
Cdd:cd15717    1 VWVPDSEAPVCMHCKKtKFTAINRRHHCRKCGAVVCGACSSKKF-LLPHQSS--KPLRVCDTCY 61

RUN domain found in RUN domain-containing protein 3B (RUNDC3B) and similar proteins; RUN domain-containing protein 3B (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. RUNDC3B contains a RUN domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013 284 NLVNICKLVVKELLEQSLRygRMLDSDHLPLQHFFIVIEHVLGHGLRPKKGLLG---PRkELWDLLQ----SVEHYCpea 356
Cdd:cd17700    1 NLITVCRFSVKTLIDRSCF--ETIDDSSPEFVNFAAILEQILSHRLKGQVTWFGyesPR-SFWDYIRvacsKVPHNC--- 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013 357 qdiTASVRDLPTVRTHIGRARAWLRIALMQKKLSDYLQALIEHREdSLFDYYEPHALMMSDEIVVIMGILVGLNVIDCNL 436
Cdd:cd17700   75 ---ICSIENMENVSSSRAKGRAWIRVALMEKRLSEYISTALRDFK-TTRRFYEDGAIVLGEEANMLAGMLLGLNAIDFSF 150

                 .
gi 599128013 437 C 437
Cdd:cd17700  151 C 151

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 599128013 284 NLVNICKLVVKELLEQSLryGRMLDSDHLPLQHFFIVIEHVLGHGLRPKKGLLGP--RKELWDLLQSVEHYCPeaQDITA 361
Cdd:cd17699    1 NLITVCRFSVKTLLEKYT--AEPIDDSSEEFVNFAAILEQILSHRFKGPVSWFSSdgQRGFWDYIRLACSKVP--NNCIS 76

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 599128013 362 SVRDLPTVRTHIGRARAWLRIALMQKKLSDYLQ-ALIEHREDSLFdyYEPHALMMSDEIVVIMGILVGLNVIDCNLC 437
Cdd:cd17699   77 SIENMENISTSRAKGRAWIRVALMEKRLSEYIAtALRDTRTTRRF--YDDGAIMLREESTVLTGMLIGLSAIDFSFC 151

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 599128013 308 DSDHLPLQHFFIVIEHVLGHGLRPKKGLLGPRKELWDLLQSVEHYCPEA----QDITASVRDLPTVRTHIGRARAWLRIA 383
Cdd:cd17682   18 DPDNPYLRPFCETLEKILRKGLKEKVSLGGRRKDYWDWLEELLKKLNKIpkslSDAVKFVKSCKKVKTNQGRGRLFIRYA 97

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 599128013 384 LMQKKLSDYLQALIEHReDSLFDYYEPHALmMSDEI 419
Cdd:cd17682   98 LNKKCLHDPVQQLVKNP-KLLSDYYSPDSI-LGNEI 131

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 599128013 812 IWAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLlnAQGQPGKPVRVCDNCY 874
Cdd:cd15727    3 PWVPDKECPVCMSCKKKFDFFKRRHHCRRCGKCFCSDCCSNKVPL--PRMCFVDPVRVCNECA 63

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 599128013 813 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPlLNAQGQPGKpVRVCDNCY 874
Cdd:cd15725    2 WMPDSSCKECYECSEKFTTFRRRHHCRLCGQIFCSRCCNQEIP-GKFIGYPGD-LRVCTYCC 61

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 599128013 822 CTACEREFNLTRRKHHCRSCGEIFCKACS--EHTLPLLNAQgqpgKPVRVCDNCY 874
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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 599128013 812 IWAPDSIATHCTACER-EFNLTRRKHHCRSCGEIFCKACSEHTLPLlnaQGQPGKPVRVCDNCY 874
Cdd:cd15755    1 VWVPDSEATVCMRCQKaKFTPVNRRHHCRKCGFVVCGPCSEKKFLL---PSQSSKPVRVCDFCY 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 599128013 813 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHtLPLlnaqgqpgkPVRVCDNCY 874
Cdd:cd15716    4 WVNDSDVPFCPDCGKKFNLARRRHHCRLCGSIMCNKCSQF-LPL---------HIRCCHHCK 55

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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 599128013 813 WAPDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPllnaQGQPGKPVRVCDNCY 874
Cdd:cd15739    4 WQHEDDVDQCPNCKTPFSVGKRKHHCRHCGKIFCSDCLTKTVP----SGPNRRPARVCDVCH 61

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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 599128013 814 APDSIATHCTACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNAQGQPGKpvrVCDNCYA 875
Cdd:cd15742    4 VPVSHVMMCMNCGSDFTLTLRRHHCHACGKIVCRNCSRNKYPLKYLKDRPAK---VCDGCFA 62

RUN domain found in sorting nexin-29 (SNX29) and similar proteins; SNX29, also called RUN domain-containing protein 2A (RUNDC2A), belongs to the sorting nexin family. Sorting nexins are a large group of proteins that are localized in the cytoplasm and have the potential for membrane association either through their lipid-binding PX domain, a phospholipid-binding motif, or through protein-protein interactions with membrane-associated protein complexes. Some sorting nexin family members have been shown to facilitate protein sorting. This model contains the RUN domain of SNX29.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013 320 VIEHVLGHGLRPKKGLLGPRKELWDLLQSVEHYCPEAQDIT--ASVRD------------LPTVRTHIGRARAWLRIALM 385
Cdd:cd17689   33 QLEAVLQHGLKTSRSPNLVSSAVTQVSGLAGSLGSAETEPTfwPFVKEhltkhelerfelLKNIWTDIGRGRAWLRSALN 112

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 599128013 386 QKKLSDYLQALIEHrEDSLFDYYEPHALMMSDEIV-VIMGILVGLNVI 432
Cdd:cd17689  113 EHSLERYLHILLSN-ENLLRQYYEDWAFLRDEERSsMLPNMAAGLGSI 159

FYVE-related domain found in uncharacterized myotubularin-related proteins mainly from eumetazoa; This family includes a group of uncharacterized myotubularin-related proteins mainly found in eumetazoa. Although their biological functions remain unclear, they share similar domain architecture that consists of an N-terminal pleckstrin homology (PH) domain, a highly conserved region related to myotubularin proteins, a C-terminal FYVE domain. The model corresponds to the FYVE domain, which resembles the FYVE-related domain as it has an altered sequence in the basic ligand binding patch.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 599128013 813 WAPDSIATHCtACEREFNLTRRKHHCRSCGEIFCKACSEHTLPLLNAQGQpgKPVRVCDNCY 874
Cdd:cd15738    3 WKSFRNVTEC-SCSTPFDHFSKKHHCWRCGNVFCTRCIDKQRALPGHLSQ--RPVPVCRACY 61

RUN domain found in pleckstrin homology domain-containing family M member 1 (PLEKHM1) and similar proteins; PLEKHM1, also called PH domain-containing family M member 1, or 162 kDa adapter protein (AP162), may act as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. This model represents the RUN domain of PLEKHM1.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 599128013 292 VVKELLEQSLRYGRMLDSDHLPLQHFFIVIEHVLGHGLRPK-----KGLLG------PRKELWDLLQSVEHycpeaQDIT 360
Cdd:cd17679   11 SVKELQLEYVSSDEVVTSSDDGANTLCCVLEAIFLHGLKDKfiskvSSVFSgdvdklPEPNFWPLLLKFSH-----RDVI 85

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 599128013 361 ASVRDLPTVRTHIGRARAWLRIALMQKKLSDYLQALIEHReDSLFDYYEPHALMMSDEIVVIM-GILVGLNVIDCNL 436
Cdd:cd17679   86 DQIEHLSQITTDVGRCRAWIRLALNDGLLESYLEAILKDK-SALKSYYNPSAFLRDPEQLDILkSLLQGLESFQFEL 161

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 599128013 821 HCTACEREFNLTRRKHHCRSCGEIFCKACSeHTLPLLNAQGQPGKpVRVCDNCY 874
Cdd:cd15745    1 ACAICAKAFSLFRRKYVCRLCGGVVCHSCS-SEDLVLSVPDTCIY-LRVCKTCY 52