VHS (Vps27/Hrs/STAM) domain of Hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs; Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) plays a role in at least three vesicle trafficking events: exocytosis, endocytosis, and endosome to lysosome trafficking. Hrs is involved in promoting rapid recycling of endocytosed signaling receptors to the plasma membrane. Together with STAM or STAM2, it comprises the ESCRT (Endosomal Sorting Complex Required for Transport)-0 machinery, which functions to bind and sequester cargoes for downstream sorting into intralumenal vesicles. Hrs contains an N-terminal VHS domain, which has a superhelical structure similar to the structure of ARM (Armadillo) repeats, a FYVE (Fab1p, YOTB, Vac1p, and EEA1) zinc finger domain, a Double Ubiquitin-Interacting Motif (DUIM), a P(S/T)XP motif that recruit ESCRT-I, a GAT (GGA and TOM) domain, and a short peptide motif near the C-terminus that recruits clathrin.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119   6 GTFERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVAN 85
Cdd:cd03569   1 SNFDKLLDKATSQLLLEPDWESILQICDLIRQGDVTPKYAVSAIKKKLNDQNPHVALYALQVLESVVKNCGTPVHDEVAT 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 71152119  86 KQTMEELKDLLKRQVEVNVRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMKVEGHVFP 143
Cdd:cd03569  81 KEFMEELRDLVKTTTSENVRNKILELIQAWAHAFRNEPKYKIVQDTYNIMKMEGYKFP 138

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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 71152119 159 DWVDAEECHRCRVQFGVMTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQL 219
Cdd:cd15720   1 EWKDGDECHRCRVQFGVFQRKHHCRACGQVFCGKCSSKSSTIPKFGIEKEVRVCDPCYEKL 61

Uncharacterized N-terminal coiled-coil domain of peptidoglycan hydrolase CwlO [Function unknown];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119 455 ELLNQLDERRLYYEGLQDKLAQIRDARGALSALR---EEHREKLRRAAEEAERQR---QIQLAQKLEIMRQKKQEYLEVQ 528
Cdd:COG3883 116 DFLDRLSALSKIADADADLLEELKADKAELEAKKaelEAKLAELEALKAELEAAKaelEAQQAEQEALLAQLSAEEAAAE 195

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119 529 RQLAIQRLQEQEKERQMRLEQQKQTVQMRAQMPAFPLPYAQLQAMPAAGGVlyQPSGPASFPSTFSPAGSVEGSPMHGVY 608
Cdd:COG3883 196 AQLAELEAELAAAEAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAASA--AGAGAAGAAGAAAGSAGAAGAAAGAAG 273

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119 609 MSQPAPAAGPYPSMPSTAADPSMVSAYMYPAGATGAQAAPQAQAGPTASPAYSSYQPTPTAGYQNVASQAPQSLPAISQP 688
Cdd:COG3883 274 AGAAAASAAGGGAGGAGGGGGGGGAASGGSGGGSGGAGGVGSGGGAGAVVGGASAGGGGGSGGGGGSSGGGSGGGGGGGG 353

                       250       260
                ....*....|....*....|....
gi 71152119 689 PQSSTMGYMGSQSVSMGYQPYNMQ 712
Cdd:COG3883 354 GGGGSSSGGGGGGVGLSVGGGYVG 377

VHS (Vps27/Hrs/STAM) domain of Hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs; Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) plays a role in at least three vesicle trafficking events: exocytosis, endocytosis, and endosome to lysosome trafficking. Hrs is involved in promoting rapid recycling of endocytosed signaling receptors to the plasma membrane. Together with STAM or STAM2, it comprises the ESCRT (Endosomal Sorting Complex Required for Transport)-0 machinery, which functions to bind and sequester cargoes for downstream sorting into intralumenal vesicles. Hrs contains an N-terminal VHS domain, which has a superhelical structure similar to the structure of ARM (Armadillo) repeats, a FYVE (Fab1p, YOTB, Vac1p, and EEA1) zinc finger domain, a Double Ubiquitin-Interacting Motif (DUIM), a P(S/T)XP motif that recruit ESCRT-I, a GAT (GGA and TOM) domain, and a short peptide motif near the C-terminus that recruits clathrin.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119   6 GTFERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVAN 85
Cdd:cd03569   1 SNFDKLLDKATSQLLLEPDWESILQICDLIRQGDVTPKYAVSAIKKKLNDQNPHVALYALQVLESVVKNCGTPVHDEVAT 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 71152119  86 KQTMEELKDLLKRQVEVNVRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMKVEGHVFP 143
Cdd:cd03569  81 KEFMEELRDLVKTTTSENVRNKILELIQAWAHAFRNEPKYKIVQDTYNIMKMEGYKFP 138

non-canonical GAT domain found in metazoan hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and similar proteins; Hrs, also called protein pp110, is a tyrosine kinase substrate in growth factor-stimulated cells. It is involved in intracellular signal transduction mediated by cytokines and growth factors. Hrs is a component of the ESCRT-0 complex that binds ubiquitin and acts as sorting machinery that recognizes ubiquitinated receptors and transfers them for further sequential lysosomal sorting/trafficking processes. Members of this family contain a non-canonical GAT (GGA and Tom1) domain consisting of two helices. A canonical GAT domain is a monomeric three-helix bundle that bind to ubiquitin. Hrs, together with another GAT domain-containing protein STAM, forms a Hrs/STAM core complex that consists of two intertwined GAT domains, each consisting of two helices from one subunit, and one from the other subunit. The two GAT domains are connected by a two-stranded coiled-coil. The Hrs/STAM complex, an intertwined GAT heterodimer, is a scaffold for binding of ubiquitinated cargo proteins and coordinating ubiquitination and deubiquitination reactions that regulate sorting.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119 406 EQFLKALQNAVTTFVNRMKSNHMRGRSITNDSAVLSLFQSINGMHPQLLELLNQLDERRLYYEGLQDKLAQIRDARGALS 485
Cdd:cd21387   1 EEFLNALRSSVEVFVNRMKSNSSRGRSIANDSAVQSLFQTLTAMHPQLLQLIQQQEEKRLYYEGLQDKLAQIREAREALD 80

                        90
                ....*....|....*.
gi 71152119 486 ALREEHREKLRRAAEE 501
Cdd:cd21387  81 ALREEHREKLRREAEE 96

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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 71152119 159 DWVDAEECHRCRVQFGVMTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQL 219
Cdd:cd15720   1 EWKDGDECHRCRVQFGVFQRKHHCRACGQVFCGKCSSKSSTIPKFGIEKEVRVCDPCYEKL 61

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 71152119    157 APDWVD---AEECHRCRVQFGVMTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQLNR 221
Cdd:smart00064   1 RPHWIPdeeVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLGIERPVRVCDDCYENLNG 68

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119  438 AVLSLFQSINGMHPQLL------ELLNQLDERRLYYEGLQDKLAQIRDARGALSALREEHREKLRRAAEEAERQRQIQLA 511
Cdd:COG4913  229 ALVEHFDDLERAHEALEdareqiELLEPIRELAERYAAARERLAELEYLRAALRLWFAQRRLELLEAELEELRAELARLE 308

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 71152119  512 QKLEIMRQK----KQEYLEVQRQLA-------------IQRLQEQEKERQMRLEQQKQTVQM 556
Cdd:COG4913  309 AELERLEARldalREELDELEAQIRgnggdrleqlereIERLERELEERERRRARLEALLAA 370

MAP7 (E-MAP-115) family; The organization of microtubules varies with the cell type and is presumably controlled by tissue-specific microtubule-associated proteins (MAPs). The 115-kDa epithelial MAP (E-MAP-115/MAP7) has been identified as a microtubule-stabilising protein predominantly expressed in cell lines of epithelial origin. The binding of this microtubule associated protein is nucleotide independent.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 71152119   488 REEHREKLRRAAEEAERQRQIQLAQKLEIMRQKKQEYLEVQRQLAIQRLQEQEKERQMRLEQQKQTVQMRAQ 559
Cdd:pfam05672  40 EERLRKEELRRRAEEERARREEEARRLEEERRREEEERQRKAEEEAEEREQREQEEQERLQKQKEEAEAKAR 111

cell envelope integrity inner membrane protein TolA; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119  499 AEEAERQRQIQLAQKLEIMRQKKQEYLEVQRQLAIQRLQEQEK------ERQMRLEQQKQTVQMRAQMPAFPLPYAQLQA 572
Cdd:PRK09510  74 AKRAEEQRKKKEQQQAEELQQKQAAEQERLKQLEKERLAAQEQkkqaeeAAKQAALKQKQAEEAAAKAAAAAKAKAEAEA 153

                 ....
gi 71152119  573 MPAA 576
Cdd:PRK09510 154 KRAA 157

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 71152119    449 MHPQLLELLNQLDERRLYYEGLQDKLAQIRDARGALSALREEHREKLRRAAEEAERQRQIQLAQKLEIMRQKKQeylEVQ 528
Cdd:TIGR02168  363 LEAELEELESRLEELEEQLETLRSKVAQLELQIASLNNEIERLEARLERLEDRRERLQQEIEELLKKLEEAELK---ELQ 439

                           90       100       110
                   ....*....|....*....|....*....|
gi 71152119    529 RQLA-IQRLQEQEKERQMRLEQQKQTVQMR 557
Cdd:TIGR02168  440 AELEeLEEELEELQEELERLEEALEELREE 469

Guanylate-binding protein, C-terminal domain; Guanylate-binding protein (GBP), C-terminal domain. Guanylate-binding proteins (GBPs) are synthesized after activation of the cell by interferons. The biochemical properties of GBPs are clearly different from those of Ras-like and heterotrimeric GTP-binding proteins. They bind guanine nucleotides with low affinity (micromolar range), are stable in their absence, and have a high turnover GTPase. In addition to binding GDP/GTP, they have the unique ability to bind GMP with equal affinity and hydrolyze GTP not only to GDP, but also to GMP. This C-terminal domain has been shown to mediate inhibition of endothelial cell proliferation by inflammatory cytokines.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 71152119 486 ALREEHREKLRRAAEEAERQRQIQLAQKLEIMRQKKQEYLEVQRQLAIQRLQEQEKErqMRLEQQKQTVQMRAQM 560
Cdd:cd16269 215 KLLEEQQRELEQKLEDQERSYEEHLRQLKEKMEEERENLLKEQERALESKLKEQEAL--LEEGFKEQAELLQEEI 287

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 71152119    452 QLLELLNQLDERRLYYEGLQDKLAQIR----DARGALSALREEhREKLRRAAEEAERQrQIQLAQKLEIMRQKKQEYLEV 527
Cdd:TIGR02168  671 SILERRREIEELEEKIEELEEKIAELEkalaELRKELEELEEE-LEQLRKELEELSRQ-ISALRKDLARLEAEVEQLEER 748

                           90       100
                   ....*....|....*....|....
gi 71152119    528 QRQL--AIQRLQEQEKERQMRLEQ 549
Cdd:TIGR02168  749 IAQLskELTELEAEIEELEERLEE 772

VHS (Vps27/Hrs/STAM) domain of Hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs; Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) plays a role in at least three vesicle trafficking events: exocytosis, endocytosis, and endosome to lysosome trafficking. Hrs is involved in promoting rapid recycling of endocytosed signaling receptors to the plasma membrane. Together with STAM or STAM2, it comprises the ESCRT (Endosomal Sorting Complex Required for Transport)-0 machinery, which functions to bind and sequester cargoes for downstream sorting into intralumenal vesicles. Hrs contains an N-terminal VHS domain, which has a superhelical structure similar to the structure of ARM (Armadillo) repeats, a FYVE (Fab1p, YOTB, Vac1p, and EEA1) zinc finger domain, a Double Ubiquitin-Interacting Motif (DUIM), a P(S/T)XP motif that recruit ESCRT-I, a GAT (GGA and TOM) domain, and a short peptide motif near the C-terminus that recruits clathrin.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119   6 GTFERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVAN 85
Cdd:cd03569   1 SNFDKLLDKATSQLLLEPDWESILQICDLIRQGDVTPKYAVSAIKKKLNDQNPHVALYALQVLESVVKNCGTPVHDEVAT 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 71152119  86 KQTMEELKDLLKRQVEVNVRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMKVEGHVFP 143
Cdd:cd03569  81 KEFMEELRDLVKTTTSENVRNKILELIQAWAHAFRNEPKYKIVQDTYNIMKMEGYKFP 138

non-canonical GAT domain found in metazoan hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and similar proteins; Hrs, also called protein pp110, is a tyrosine kinase substrate in growth factor-stimulated cells. It is involved in intracellular signal transduction mediated by cytokines and growth factors. Hrs is a component of the ESCRT-0 complex that binds ubiquitin and acts as sorting machinery that recognizes ubiquitinated receptors and transfers them for further sequential lysosomal sorting/trafficking processes. Members of this family contain a non-canonical GAT (GGA and Tom1) domain consisting of two helices. A canonical GAT domain is a monomeric three-helix bundle that bind to ubiquitin. Hrs, together with another GAT domain-containing protein STAM, forms a Hrs/STAM core complex that consists of two intertwined GAT domains, each consisting of two helices from one subunit, and one from the other subunit. The two GAT domains are connected by a two-stranded coiled-coil. The Hrs/STAM complex, an intertwined GAT heterodimer, is a scaffold for binding of ubiquitinated cargo proteins and coordinating ubiquitination and deubiquitination reactions that regulate sorting.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119 406 EQFLKALQNAVTTFVNRMKSNHMRGRSITNDSAVLSLFQSINGMHPQLLELLNQLDERRLYYEGLQDKLAQIRDARGALS 485
Cdd:cd21387   1 EEFLNALRSSVEVFVNRMKSNSSRGRSIANDSAVQSLFQTLTAMHPQLLQLIQQQEEKRLYYEGLQDKLAQIREAREALD 80

                        90
                ....*....|....*.
gi 71152119 486 ALREEHREKLRRAAEE 501
Cdd:cd21387  81 ALREEHREKLRREAEE 96

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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 71152119 159 DWVDAEECHRCRVQFGVMTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQL 219
Cdd:cd15720   1 EWKDGDECHRCRVQFGVFQRKHHCRACGQVFCGKCSSKSSTIPKFGIEKEVRVCDPCYEKL 61

VHS (Vps27/Hrs/STAM) domain family; The VHS domain is present in Vps27 (Vacuolar Protein Sorting), Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) and STAM (Signal Transducing Adaptor Molecule). It has a superhelical structure similar to that of the ARM (Armadillo) repeats and is present at the N-termini of proteins involved in intracellular membrane trafficking. There are four general groups of VHS domain containing proteins based on their association with other domains. The first group consists of proteins of the STAM/EAST/Hbp family, which has the domain composition of VHS-SH3-ITAM. The second consists of proteins with a FYVE domain C-terminal to VHS. The third consists of GGA proteins with a domain composition of VHS-GAT (GGA and TOM)-GAE (Gamma-Adaptin Ear) domain. The fourth consists of proteins with a VHS domain alone or with domains other than those mentioned above. In GGA proteins, VHS domains are involved in cargo recognition in trans-Golgi, thereby having a general membrane targeting/cargo recognition role in vesicular trafficking.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119   8 FERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVANKQ 87
Cdd:cd03561   1 VEELVEKATSESLTEPDWALNLEICDLVNSDPAQAKDAVRALRKRLQSKNPKVQLLALTLLETLVKNCGAPFHSEVASRD 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 71152119  88 TMEEL-KDLLKRQVEVNVRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMK 136
Cdd:cd03561  81 FLQELvKLVKKKKTSPEVREKALALIQEWAEAFQGDGRLPLFYDTYQQLR 130

VHS (Vps27/Hrs/STAM) domain of Vacuolar protein sorting-associated protein 27; Vacuolar protein sorting-associated protein 27 (Vps27 or Vps27p) is also called Golgi retention defective protein 11, and is the yeast homolog of Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate). Together with class E vacuolar protein-sorting machinery protein HSE1, it comprises the ESCRT-0 complex, the sorting receptor for ubiquitinated cargo proteins at the multivesicular body (MVB). The complex directly binds to ubiquitinated transmembrane proteins and recruits both ubiquitin ligases and deubiquitinating enzymes. It is also required the efficient recycling of late Golgi proteins including the carboxypeptidase Y (CPY) sorting receptor, Vps10. Vps27 contain similar domains and motifs to Hrs; it contains an N-terminal VHS domain, which has a superhelical structure similar to the structure of ARM (Armadillo) repeats, a FYVE (Fab1p, YOTB, Vac1p, and EEA1) zinc finger domain, two Ubiquitin-Interacting Motifs (UIMs), a GAT (GGA and TOM) domain, two a P(S/T)XP motifs that recruit ESCRT-I, and a short peptide motif near the C-terminus that recruits clathrin.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119   8 FERLLDKATSQLLL--ETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVAN 85
Cdd:cd16979   3 FDELIEKATSESIPngEEDLALALEISDLIRSKSVPPKDAMRSLKKRILHKNPNVQLLALKLTDVCVKNGGDHFLVEIAS 82

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 71152119  86 KQTMEELKDLLKRQ-VEVNVRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMKVEGHVFP 143
Cdd:cd16979  83 REFMDNLVSLIRSTgVNPEVKEKILRLIQEWALAFKSKSQLSYVVEVYKKLKSEGIEFP 141

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 71152119    157 APDWVD---AEECHRCRVQFGVMTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQLNR 221
Cdd:smart00064   1 RPHWIPdeeVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLGIERPVRVCDDCYENLNG 68

non-canonical GAT domain found in metazoan signal transducing adapter molecules (STAMs), fungal vacuolar protein sorting-associated protein 27 (Vps27), and similar proteins; This family includes several components of the ESCRT-0 complex, including STAMs, hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), as well as vacuolar protein sorting-associated protein 27 (Vps27) and class E vacuolar protein-sorting machinery protein Hse1 from fungi. The ESCRT-0 complex binds ubiquitin and acts as a sorting machinery that recognizes ubiquitinated receptors and transfers them for further sequential lysosomal sorting/trafficking processes. Members in this family contain a non-canonical GAT (GGA and Tom1) domain consisting of two helices. By contrast, a canonical GAT domain is a monomeric three-helix bundle that bind to ubiquitin. Hrs together with STAM forms a Hrs/STAM core complex. Vps27, together with Hse1, forms a Vps27/Hse1 core complex. Those complexes consist of two intertwined non-canonical GAT domains, each consisting of two helices from one subunit, and one from the other subunit. The intertwined GAT heterodimer acts as a scaffold for binding of ubiquitinated cargo proteins and coordinating ubiquitination and deubiquitination reactions that regulate sorting.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 71152119 410 KALQNAVTTFVNRMKSNHMRGRS-ITNDSAVLSLFQSINGMHPQLLELLNQLDERRLYYEGLQDKLAQIRDARGALSAL 487
Cdd:cd21384   1 FSQKDTIDQLHNSLNSASKRGNSeILQDPHLLDLYQSVTPMRPQLTE*LNDYAKKKEDLLELNQKLAEAERSYNQL*DR 79

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 71152119   160 WV---DAEECHRCRVQFGVMTRKHHCRACGQIFCGKCSSK-YSTIPKFGIEKEVRVCEPCYEQLNR 221
Cdd:pfam01363   3 WVpdsSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKkISLLPELGSNKPVRVCDACYDTLQK 68

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 71152119 158 PDWVDAEECHRCRVQFGVMTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCY 216
Cdd:cd15735   1 PEWVDSDVCMRCRTAFTFTNRKHHCRNCGGVFCQQCSSKSLPLPHFGINQPVRVCDGCY 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 71152119 165 ECHRCRVQFGVMTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCY 216
Cdd:cd00065   1 RCMLCGKKFSLFRRRHHCRRCGRVFCSKCSSKKLPLPSFGSGKPVRVCDSCY 52

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 71152119 160 WVD---AEECHRCRVQFGVMTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQL 219
Cdd:cd15719   3 WVKdegGDSCTGCSVRFSLTERRHHCRNCGQLFCSKCSRFESEIRRLRISRPVRVCQACYNIL 65

VHS (Vps27/Hrs/STAM) domain of Target of Myb protein 1; Tom1 (Target of myb1 - retroviral oncogene) is a novel negative regulator of interleukin-1 and tumor necrosis factor-induced signaling pathways. It also plays important roles in protein-degradation systems in Alzheimer's disease pathogenesis. Tom1 contains VHS and GAT domains in the N-terminal and central region, respectively. The VHS domain has a superhelical structure similar to the structure of the ARM repeats and is present at the very N-termini of proteins. It is a right-handed superhelix of eight alpha helices. The VHS domain has been found in a number of proteins, some of which have been implicated in intracellular trafficking and sorting. The VHS domain of Tom1 is essential for its function as a negative regulator.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119  10 RLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKK-VNDKNPHVALYALEVMESVVKNCGQTVHDEVANKQT 88
Cdd:cd16995   4 QRIEKATDGSLQSEDWGLNMEICDIINETEEGPKDAIRAIKKRiVGNKNFREVMLALTVLETCVKNCGHRFHVLVASQDF 83

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 71152119  89 MEE--LKDLL-KRQVEVNVRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMKVEG 139
Cdd:cd16995  84 VEGvlVKTILpKNNPPAIVHDKVLNLIQAWADAFRSSPDLTGVVTVYEDLRRKG 137

VHS (Vps27/Hrs/STAM) domain of GGA (Golgi-localized, Gamma-ear-containing, Arf-binding) subfamily; GGA (Golgi-localized, Gamma-ear-containing, Arf-binding) comprises a subfamily of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins involved in membrane trafficking between the Trans-Golgi Network (TGN) and endosomes. The VHS domain has a superhelical structure similar to the structure of the ARM (Armadillo) repeats and is present at the N-termini of proteins. GGA proteins have a multidomain structure consisting of an N-terminal VHS domain linked by a short proline-rich linker to a GAT (GGA and TOM) domain, which is followed by a long flexible linker to the C-terminal appendage, GAE (Gamma-Adaptin Ear) domain. The VHS domain of GGA proteins binds to the acidic-cluster dileucine (DxxLL) motif found on the cytoplasmic tails of cargo proteins trafficked between the Trans-Golgi Network and the endosomal system.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119   9 ERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVANKQT 88
Cdd:cd16977   2 ERWINRATNPSNAEPDWALILGFCDQINEDGEGPRDAARLLAHKIQSPQEWEAIQALTVLEVCMKNCGYRFHLEVGKFRF 81

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 71152119  89 MEEL------KDLLKRQVEvNVRNKILYLIQAWAHAFrnePKYKVVQDTYQIMK 136
Cdd:cd16977  82 LNELikvvspKYLGSRRSE-KVKRKILELLYSWTVTL---PEEGKIRDAYQMLK 131

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 71152119 158 PDWVD---AEECHRCRVQFGVMTRKHHCRACGQIFCGKCSSKYSTIPKFgiEKEVRVCEPCYEQL 219
Cdd:cd15730   1 RKWADdeeVQNCMACGKGFSVTVRKHHCRQCGNIFCNECSSKTATTPSS--KKPVRVCDACFDDL 63

VHS (Vps27/Hrs/STAM) domain of TOM1-like protein 2; TOM1-like protein 2 (Tom1L2) is a member of the Tom1 (Target of myb1) subfamily, characterized by the presence of a VHS (Vps27p/Hrs/Stam) domain in the N-terminal portion followed by a GAT (GGA and Tom) domain. They are novel regulators for post-Golgi trafficking and signaling. Studies in Tom1L2 hypomorphic mice suggest that Tom1L2 may play roles in immune responses and tumor suppression. The VHS domain has a superhelical structure similar to the structure of the ARM repeats and is present at the very N-termini of proteins. It is a right-handed superhelix of eight alpha helices. The VHS domain has been found in a number of proteins, some of which have been implicated in intracellular trafficking and sorting.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119  12 LDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVN-DKNPHVALYALEVMESVVKNCGQTVHDEVANKQTME 90
Cdd:cd16996   6 IEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNgNKNYREVMLALTVLETCVKNCGHRFHVLVASRDFID 85

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 71152119  91 ELkdLLKRQVEVN-----VRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMKVEG 139
Cdd:cd16996  86 GV--LVKIISPKNnpptiVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKG 137

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 71152119 157 APDWV---DAEECHRCRVQFGVMTRKHHCRACGQIFCGKCSSKYSTIPkFGIEKEVRVCEPCYEQL 219
Cdd:cd15729   4 APVWVpdsEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLE-YLDNKEARVCVPCYQTL 68

VHS (Vps27/Hrs/STAM) domain of fungal GGA (Golgi-localized, Gamma-ear-containing, Arf-binding) proteins; GGA (Golgi-localized, Gamma-ear-containing, Arf-binding) comprises a subfamily of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins involved in membrane trafficking between the Trans-Golgi Network (TGN) and endosomes. Yeast GGAs facilitate the specific and direct delivery of vacuolar sorting receptor Vps10p and the processing protease Kex2p from the TGN to the late endosome/prevacuolar compartment (PVC). The VHS domain has a superhelical structure similar to the structure of the ARM (Armadillo) repeats and is present at the N-termini of proteins. GGA proteins have a multidomain structure consisting of an N-terminal VHS domain linked by a short proline-rich linker to a GAT (GGA and TOM) domain, which is followed by a long flexible linker to the C-terminal appendage, GAE (Gamma-Adaptin Ear) domain. The VHS domain of GGA proteins binds to the acidic-cluster dileucine (DxxLL) motif found on the cytoplasmic tails of cargo proteins trafficked between the Trans-Golgi Network and the endosomal system.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119   9 ERLLDKATSQLLLETDWESILQICDLI--RQGDTqAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVANK 86
Cdd:cd16998   2 QRYIERACDPSLEEPNLALNLEIADLIneKQGNT-PREAAFAIVRLVNSRNPTVALLALHLLDVCVKNCGYPFHLQIASK 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 71152119  87 qtmEELKDLLKR------QVEVNVRNKILYLIQAWAHAFRNEPKYKV----VQDTYQIMK 136
Cdd:cd16998  81 ---EFLNELVRRfperppSRLNPVQHKILELIEEWKQTLCKTSRYKEdlghIRDMHRLLS 137

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 71152119 157 APDWVDAEECHRC---RVQFGVMTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYE 217
Cdd:cd15727   1 EPPWVPDKECPVCmscKKKFDFFKRRHHCRRCGKCFCSDCCSNKVPLPRMCFVDPVRVCNECAL 64