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 226693388   6 GTFERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVAN 85
Cdd:cd03569    1 SNFDKLLDKATSQLLLEPDWESILQICDLIRQGDVTPKYAVSAIKKKLNDQNPHVALYALQVLESVVKNCGTPVHDEVAT 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 226693388  86 KQTMEELKELLKRQVEVNVRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMKVEGHVFP 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 226693388 159 DWVDAEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQL 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 226693388 454 ELLNQLDERRLYYEGLQDKLAQIRDARGALSALR---EEHREKLRRAAEEAERQR---QIQLAQKLEIMRQKKQEYLEVQ 527
Cdd:COG3883  116 DFLDRLSALSKIADADADLLEELKADKAELEAKKaelEAKLAELEALKAELEAAKaelEAQQAEQEALLAQLSAEEAAAE 195

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 226693388 528 RQLAIQRLQEQEKERQMRLEQQKQTVQMRAQMPAFPLPYAQLQAMPTAGGVLYQPSGPTSFPATFSPAGSVEGSPMHGVY 607
Cdd:COG3883  196 AQLAELEAELAAAEAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAASAAGAGAAGAAGAAAGSAGAAGAAAGAAGAG 275

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 226693388 608 MSQPAPATGPYPSmpGTTADPSMVSAYMYPTGAPGAQAAPQAQAGPTTSPAYSSYQPTPTPGYQSVASQAPQSLPAISQP 687
Cdd:COG3883  276 AAAASAAGGGAGG--AGGGGGGGGAASGGSGGGSGGAGGVGSGGGAGAVVGGASAGGGGGSGGGGGSSGGGSGGGGGGGG 353

                        250       260
                 ....*....|....*....|....
gi 226693388 688 PQTSNIGYMGSQPMSMGYQPYNMQ 711
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 226693388   6 GTFERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVAN 85
Cdd:cd03569    1 SNFDKLLDKATSQLLLEPDWESILQICDLIRQGDVTPKYAVSAIKKKLNDQNPHVALYALQVLESVVKNCGTPVHDEVAT 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 226693388  86 KQTMEELKELLKRQVEVNVRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMKVEGHVFP 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 226693388 405 EQFLKALQNAVSTFVNRMKSNHMRGRSITNDSAVLSLFQSINTMHPQLLELLNQLDERRLYYEGLQDKLAQIRDARGALS 484
Cdd:cd21387    1 EEFLNALRSSVEVFVNRMKSNSSRGRSIANDSAVQSLFQTLTAMHPQLLQLIQQQEEKRLYYEGLQDKLAQIREAREALD 80

                         90
                 ....*....|....*.
gi 226693388 485 ALREEHREKLRRAAEE 500
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 226693388 159 DWVDAEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQL 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 226693388   157 APDWVD---AEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQLNK 221
Cdd:smart00064   1 RPHWIPdeeVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLGIERPVRVCDDCYENLNG 68

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 226693388 453 LELLNQLDERR-----LYYEGLQDKLAQIRDARGALSALREEHREKLRRAAEEAERQRQIQLAQKLEIMRQKKQEYLEVQ 527
Cdd:COG1196  216 RELKEELKELEaelllLKLRELEAELEELEAELEELEAELEELEAELAELEAELEELRLELEELELELEEAQAEEYELLA 295

                         90       100       110
                 ....*....|....*....|....*....|.
gi 226693388 528 RQLAIQRLQEQEKERQMRLEQQKQTVQMRAQ 558
Cdd:COG1196  296 ELARLEQDIARLEERRRELEERLEELEEELA 326

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 226693388  487 REEHREKLRRAAEEAERQRQIQLAQKLEIMRQKKQEYLEVQRQLAIQRLQEQEKERQMRLEQQKQTVQMRAQ 558
Cdd:pfam05672  40 EERLRKEELRRRAEEERARREEEARRLEEERRREEEERQRKAEEEAEEREQREQEEQERLQKQKEEAEAKAR 111

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 226693388   438 VLSLFQSINTMHPQLLELLNQLDERRLYYEGLQDKLAQIRDARGALSALREEHREKLRRAAEEAERQRQIQLAQKLEIMR 517
Cdd:TIGR02168  353 LESLEAELEELEAELEELESRLEELEEQLETLRSKVAQLELQIASLNNEIERLEARLERLEDRRERLQQEIEELLKKLEE 432

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|
gi 226693388   518 QKKQeylEVQRQLA-IQRLQEQEKERQMRLEQQKQTVQMR 556
Cdd:TIGR02168  433 AELK---ELQAELEeLEEELEELQEELERLEEALEELREE 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 226693388 485 ALREEHREKLRRAAEEAERQRQIQLAQKLEIMRQKKQEYLEVQRQLAIQRLQEQEKErqMRLEQQKQTVQMRAQM 559
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 226693388   443 QSINTMHPQLLELLNQLDERRLYYEGLQDKLAQIRDARGALSALREEHREKLRRAAEEAER--QRQIQLAQKLEIMRQKK 520
Cdd:TIGR02168  684 EKIEELEEKIAELEKALAELRKELEELEEELEQLRKELEELSRQISALRKDLARLEAEVEQleERIAQLSKELTELEAEI 763

                           90       100       110
                   ....*....|....*....|....*....|....*...
gi 226693388   521 QEYLEvQRQLAIQRLQEQEKERQmRLEQQKQTVQMRAQ 558
Cdd:TIGR02168  764 EELEE-RLEEAEEELAEAEAEIE-ELEAQIEQLKEELK 799

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 226693388   6 GTFERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVAN 85
Cdd:cd03569    1 SNFDKLLDKATSQLLLEPDWESILQICDLIRQGDVTPKYAVSAIKKKLNDQNPHVALYALQVLESVVKNCGTPVHDEVAT 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 226693388  86 KQTMEELKELLKRQVEVNVRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMKVEGHVFP 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 226693388 405 EQFLKALQNAVSTFVNRMKSNHMRGRSITNDSAVLSLFQSINTMHPQLLELLNQLDERRLYYEGLQDKLAQIRDARGALS 484
Cdd:cd21387    1 EEFLNALRSSVEVFVNRMKSNSSRGRSIANDSAVQSLFQTLTAMHPQLLQLIQQQEEKRLYYEGLQDKLAQIREAREALD 80

                         90
                 ....*....|....*.
gi 226693388 485 ALREEHREKLRRAAEE 500
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 226693388 159 DWVDAEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQL 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 226693388   8 FERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVANKQ 87
Cdd:cd03561    1 VEELVEKATSESLTEPDWALNLEICDLVNSDPAQAKDAVRALRKRLQSKNPKVQLLALTLLETLVKNCGAPFHSEVASRD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 226693388  88 TMEEL-KELLKRQVEVNVRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMK 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 226693388   8 FERLLDKATSQLLL--ETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVAN 85
Cdd:cd16979    3 FDELIEKATSESIPngEEDLALALEISDLIRSKSVPPKDAMRSLKKRILHKNPNVQLLALKLTDVCVKNGGDHFLVEIAS 82

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 226693388  86 KQTMEELKELLKRQ-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 226693388   157 APDWVD---AEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQLNK 221
Cdd:smart00064   1 RPHWIPdeeVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLGIERPVRVCDDCYENLNG 68

VHS (Vps27/Hrs/STAM) domain of the STAM (Signal Transducing Adaptor Molecule) subfamily; STAM (Signal Transducing Adaptor Molecule) subfamily members have at their N-termini a VHS domain, which is involved in cytokine-mediated intracellular signal transduction and has a superhelical structure similar to the structure of ARM (Armadillo) repeats, followed by a Ubiquitin-Interacting Motif (UIM) and a SH3 (Src Homology 3) domain, which is a well-established protein-protein interaction domain, and a GAT (GGA and TOM) domain. At the C-termini of most vertebrate STAMs, an Immunoreceptor Tyrosine-based Activation Motif (ITAM) is present, which mediates the binding of HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) in endocytic and exocytic machineries. STAM is a component of the ESCRT (Endosomal Sorting Complex Required for Transport)-0 machinery and together with Hrs, functions to bind and sequester cargoes for downstream sorting into intralumenal vesicles. Jawed vertebrates have two STAM subfamily members, STAM1 and STAM2.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 226693388   8 FERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVANKQ 87
Cdd:cd03568    1 FDQDVEKATSEKNTSENWSLILDICDKVGRSPNGAKDCLKSIMKRLNHKDPHVALQALTLLDACVKNCGKIFHLEVCSRD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 226693388  88 TMEELKELL-KRQVEvnVRNKILYLIQAWAHA-FRNEPKYKVVQDTYQIMKVEG 139
Cdd:cd03568   81 FESELRKLLtKSHPK--VAEKLKELLKKWAEEeFKDDPQLSLIPSLYKKLKAEG 132

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 226693388  160 WV---DAEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSK-YSTIPKFGIEKEVRVCEPCYEQLNK 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 226693388 158 PDWVDAEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCY 216
Cdd:cd15735    1 PEWVDSDVCMRCRTAFTFTNRKHHCRNCGGVFCQQCSSKSLPLPHFGINQPVRVCDGCY 59

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 226693388 156 RAPDWV---DAEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCY 216
Cdd:cd15731    1 DPPLWVpdeACPQCMACSAPFTVLRRRHHCRNCGKIFCSRCSSNSVPLPRYGQMKPVRVCNHCF 64

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 226693388 160 WVD---AEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQL 219
Cdd:cd15719    3 WVKdegGDSCTGCSVRFSLTERRHHCRNCGQLFCSKCSRFESEIRRLRISRPVRVCQACYNIL 65

FYVE domain found in WD40 repeat and FYVE domain-containing protein WDFY1 and WDFY2, and similar proteins; This family includes WD40 repeat and FYVE domain-containing protein WDFY1 and WDFY2. WDFY1, also termed FYVE domain containing protein localized to endosomes-1 (FENS-1), or phosphoinositide-binding protein 1, or zinc finger FYVE domain-containing protein 17, is a novel single FYVE domain containing protein that binds phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) with high specificity over other phosphoinositides. WDFY1 to early endosomes requires an intact FYVE domain and is inhibited by wortmannin, a PI3-kinase inhibitor. WDFY2, also termed zinc finger FYVE domain-containing protein 22, or ProF (propeller-FYVE protein), is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein that is localized to a distinct subset of early endosomes close to the plasma membrane. It interacts preferentially with endogenous serine/threonine kinase Akt2, but not Akt1, and plays a specific role in modulating signaling through Akt downstream of the interaction of this kinase with the endosomal proteins APPL (adaptor protein containing PH domain, PTB domain, and leucine zipper motif). In addition to Akt, WDFY2 serves as a binding partner for protein kinase C, zeta (PRKCZ), and its substrate vesicle-associated membrane protein 2 (VAMP2), and is involved in vesicle cycling in various secretory pathways. Moreover, Silencing of WDFY2 by siRNA produces a strong inhibition of endocytosis. Both WDFY1 and WDFY2 contain a FYVE domain and multiple WD-40 repeats.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 226693388 158 PDWVDAEECHRCRVQF-----------GVVTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCY 216
Cdd:cd15718    1 PEWAESDNCQKCSRPFfwnfkqmwekkTLGVRQHHCRKCGKAVCDKCSSNRSTIPVMGFEFPVRVCNECY 70

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 226693388 158 PDWVD---AEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFgiEKEVRVCEPCYEQL 219
Cdd:cd15730    1 RKWADdeeVQNCMACGKGFSVTVRKHHCRQCGNIFCNECSSKTATTPSS--KKPVRVCDACFDDL 63

VHS (Vps27/Hrs/STAM) domain of Signal Transducing Adapter Molecule 1; Signal Transducing Adapter Molecule 1 (STAM1) is part of a crucial regulatory axis for the ventral axonal trajectory of developing spinal motor neurons. It forms a complex with beta-arrestin, which regulates lysosomal trafficking of the chemokine receptor CXCR4 and also mediates CXCR4-dependent chemotaxis. STAM (Signal Transducing Adaptor Molecule) subfamily members have at their N-termini a VHS domain, which is involved in cytokine-mediated intracellular signal transduction and has a superhelical structure similar to the structure of ARM (Armadillo) repeats, followed by a Ubiquitin-Interacting Motif (UIM) and a SH3 (Src Homology 3) domain, which is a well-established protein-protein interaction domain, and a GAT (GGA and TOM) domain. At the C-termini of most vertebrate STAMS, an Immunoreceptor Tyrosine-based Activation Motif (ITAM) is present, which mediates the binding of HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) in endocytic and exocytic machineries. STAM is a component of the ESCRT (Endosomal Sorting Complex Required for Transport)-0 machinery and together with Hrs, functions to bind and sequester cargoes for downstream sorting into intralumenal vesicles.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 226693388   8 FERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHVALYALEVMESVVKNCGQTVHDEVANKQ 87
Cdd:cd17000    1 FDQDVEKATSEMNTAEDWGLILDICDKVGQSRTGPKDCLRSIMRRVNHKDPHVAMQALTLLGACVSNCGKIFHLEVCSRD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 226693388  88 TMEELKELLKRQvEVNVRNKILYLIQAWAHAFRNEPKYKVVQDTYQIMKVEG 139
Cdd:cd17000   81 FASEVSNVLNKG-HPKVCEKLKALMVEWTEEFKNDPQLSLISAMIKNLKEQG 131

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 226693388  12 LDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVN-DKNPHVALYALEVMESVVKNCGQTVHDEVANKQTME 90
Cdd:cd16996    6 IEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNgNKNYREVMLALTVLETCVKNCGHRFHVLVASRDFID 85

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 226693388  91 ELkeLLKRQVEVN-----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 226693388 157 APDWV---DAEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPkFGIEKEVRVCEPCYEQL 219
Cdd:cd15729    4 APVWVpdsEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLE-YLDNKEARVCVPCYQTL 68

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 226693388 159 DWV---DAEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCY 216
Cdd:cd15734    1 YWVpdsEIKECSVCKRPFSPRLSKHHCRACGQGVCDDCSKNRRPVPSRGWDHPVRVCDPCA 61

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 226693388 157 APDWVDAEECHRC---RVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYE 217
Cdd:cd15727    1 EPPWVPDKECPVCmscKKKFDFFKRRHHCRRCGKCFCSDCCSNKVPLPRMCFVDPVRVCNECAL 64

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 226693388 160 WVD---AEECHRCRVQFGVVTRKHHCRACGQIFCGKCSSKYSTIPKFGieKEVRVCEPCY 216
Cdd:cd15721    1 WADdkeVTHCQQCEKEFSLSRRKHHCRNCGGIFCNSCSDNTMPLPSSA--KPVRVCDTCY 58