HRS_DROME
ID HRS_DROME Reviewed; 760 AA.
AC Q960X8; A4V018; Q8IGU6; Q9VQF2; Q9VQF3;
DT 26-APR-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 169.
DE RecName: Full=Hepatocyte growth factor-regulated tyrosine kinase substrate;
GN Name=Hrs; ORFNames=CG2903;
OS Drosophila melanogaster (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=7227 {ECO:0000312|EMBL:AAK93213.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B), FUNCTION, SUBCELLULAR LOCATION,
RP DEVELOPMENTAL STAGE, AND INTERACTION WITH UBI-P63E.
RC STRAIN=Berkeley; TISSUE=Embryo;
RX PubMed=11832215; DOI=10.1016/s0092-8674(02)00611-6;
RA Lloyd T.E., Atkinson R., Wu M.N., Zhou Y., Pennetta G., Bellen H.J.;
RT "Hrs regulates endosome membrane invagination and tyrosine kinase receptor
RT signaling in Drosophila.";
RL Cell 108:261-269(2002).
RN [2] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Berkeley {ECO:0000269|PubMed:10731132};
RX PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA Venter J.C.;
RT "The genome sequence of Drosophila melanogaster.";
RL Science 287:2185-2195(2000).
RN [3] {ECO:0000305}
RP GENOME REANNOTATION, AND ALTERNATIVE SPLICING.
RC STRAIN=Berkeley;
RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT review.";
RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN [4] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B).
RC STRAIN=Berkeley {ECO:0000269|PubMed:12537569};
RC TISSUE=Embryo {ECO:0000269|PubMed:12537569};
RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA Celniker S.E.;
RT "A Drosophila full-length cDNA resource.";
RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-300 AND SER-302, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RC TISSUE=Embryo;
RX PubMed=18327897; DOI=10.1021/pr700696a;
RA Zhai B., Villen J., Beausoleil S.A., Mintseris J., Gygi S.P.;
RT "Phosphoproteome analysis of Drosophila melanogaster embryos.";
RL J. Proteome Res. 7:1675-1682(2008).
RN [6] {ECO:0000305}
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS), AND HOMODIMERIZATION.
RX PubMed=10693761; DOI=10.1016/s0092-8674(00)80680-7;
RA Mao Y., Nickitenko A., Duan X., Lloyd T.E., Wu M.N., Bellen H.,
RA Quiocho F.A.;
RT "Crystal structure of the VHS and FYVE tandem domains of Hrs, a protein
RT involved in membrane trafficking and signal transduction.";
RL Cell 100:447-456(2000).
CC -!- FUNCTION: Essential role in endosome membrane invagination and
CC formation of multivesicular bodies, MVBs. Required during gastrulation
CC and appears to regulate early embryonic signaling pathways. Inhibits
CC tyrosine kinase receptor signaling by promoting degradation of the
CC tyrosine-phosphorylated, active receptor, potentially by sorting
CC activated receptors into MVBs. The MVBs are then trafficked to the
CC lysosome where their contents are degraded.
CC {ECO:0000269|PubMed:11832215}.
CC -!- SUBUNIT: Homodimer; in vitro. Interacts with ubiquitin.
CC {ECO:0000269|PubMed:10693761, ECO:0000269|PubMed:11832215}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cell cortex
CC {ECO:0000269|PubMed:11832215}. Cytoplasm, perinuclear region
CC {ECO:0000269|PubMed:11832215}. Note=Locates to vesicles present in the
CC perinuclear regions of muscle cells and in the periphery of Garland
CC cells of third-instar larvae.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=B; Synonyms=C;
CC IsoId=Q960X8-1; Sequence=Displayed;
CC Name=A;
CC IsoId=Q960X8-2; Sequence=VSP_029168, VSP_029169;
CC -!- DEVELOPMENTAL STAGE: Expressed both maternally and zygotically
CC throughout development. {ECO:0000269|PubMed:11832215}.
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DR EMBL; AY071846; AAL60055.1; -; mRNA.
DR EMBL; AE014134; AAF51221.2; -; Genomic_DNA.
DR EMBL; AE014134; AAF51222.1; -; Genomic_DNA.
DR EMBL; AE014134; AAN10412.2; -; Genomic_DNA.
DR EMBL; AY051789; AAK93213.1; -; mRNA.
DR EMBL; BT001591; AAN71346.1; -; mRNA.
DR RefSeq; NP_525099.3; NM_080360.5. [Q960X8-1]
DR RefSeq; NP_722830.2; NM_164496.1. [Q960X8-1]
DR RefSeq; NP_722831.1; NM_164497.1. [Q960X8-2]
DR PDB; 1DVP; X-ray; 2.00 A; A=1-219.
DR PDBsum; 1DVP; -.
DR AlphaFoldDB; Q960X8; -.
DR SMR; Q960X8; -.
DR BioGRID; 59683; 59.
DR DIP; DIP-32844N; -.
DR IntAct; Q960X8; 6.
DR STRING; 7227.FBpp0088692; -.
DR iPTMnet; Q960X8; -.
DR PaxDb; Q960X8; -.
DR PRIDE; Q960X8; -.
DR EnsemblMetazoa; FBtr0089749; FBpp0088690; FBgn0031450. [Q960X8-2]
DR EnsemblMetazoa; FBtr0089750; FBpp0088691; FBgn0031450. [Q960X8-1]
DR EnsemblMetazoa; FBtr0089751; FBpp0088692; FBgn0031450. [Q960X8-1]
DR GeneID; 33458; -.
DR KEGG; dme:Dmel_CG2903; -.
DR CTD; 33458; -.
DR FlyBase; FBgn0031450; Hrs.
DR VEuPathDB; VectorBase:FBgn0031450; -.
DR eggNOG; KOG1818; Eukaryota.
DR GeneTree; ENSGT00940000158297; -.
DR HOGENOM; CLU_013062_0_0_1; -.
DR InParanoid; Q960X8; -.
DR OMA; PHSSCYS; -.
DR PhylomeDB; Q960X8; -.
DR Reactome; R-DME-182971; EGFR downregulation.
DR Reactome; R-DME-432720; Lysosome Vesicle Biogenesis.
DR Reactome; R-DME-5689880; Ub-specific processing proteases.
DR Reactome; R-DME-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-DME-8856828; Clathrin-mediated endocytosis.
DR Reactome; R-DME-9013420; RHOU GTPase cycle.
DR Reactome; R-DME-917729; Endosomal Sorting Complex Required For Transport (ESCRT).
DR Reactome; R-DME-9706019; RHOBTB3 ATPase cycle.
DR SignaLink; Q960X8; -.
DR BioGRID-ORCS; 33458; 0 hits in 1 CRISPR screen.
DR EvolutionaryTrace; Q960X8; -.
DR GenomeRNAi; 33458; -.
DR PRO; PR:Q960X8; -.
DR Proteomes; UP000000803; Chromosome 2L.
DR Bgee; FBgn0031450; Expressed in adult Malpighian tubule (Drosophila) and 25 other tissues.
DR ExpressionAtlas; Q960X8; baseline and differential.
DR Genevisible; Q960X8; DM.
DR GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IEA:GOC.
DR GO; GO:0005769; C:early endosome; IBA:GO_Central.
DR GO; GO:0005768; C:endosome; IDA:FlyBase.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0035091; F:phosphatidylinositol binding; IEA:InterPro.
DR GO; GO:0043130; F:ubiquitin binding; IDA:FlyBase.
DR GO; GO:0045022; P:early endosome to late endosome transport; IMP:FlyBase.
DR GO; GO:0032456; P:endocytic recycling; IMP:FlyBase.
DR GO; GO:0006897; P:endocytosis; IMP:FlyBase.
DR GO; GO:0016197; P:endosomal transport; IMP:FlyBase.
DR GO; GO:0032509; P:endosome transport via multivesicular body sorting pathway; IMP:FlyBase.
DR GO; GO:1990182; P:exosomal secretion; IMP:FlyBase.
DR GO; GO:0045879; P:negative regulation of smoothened signaling pathway; IMP:FlyBase.
DR GO; GO:0120177; P:negative regulation of torso signaling pathway; IMP:FlyBase.
DR GO; GO:0016322; P:neuron remodeling; IGI:FlyBase.
DR GO; GO:1903688; P:positive regulation of border follicle cell migration; IMP:FlyBase.
DR GO; GO:0045752; P:positive regulation of Toll signaling pathway; IMP:FlyBase.
DR GO; GO:0061357; P:positive regulation of Wnt protein secretion; IMP:FlyBase.
DR GO; GO:0031623; P:receptor internalization; IMP:FlyBase.
DR GO; GO:0051726; P:regulation of cell cycle; IGI:FlyBase.
DR GO; GO:2000274; P:regulation of epithelial cell migration, open tracheal system; IMP:FlyBase.
DR Gene3D; 1.25.40.90; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR008942; ENTH_VHS.
DR InterPro; IPR017073; HGS/VPS27.
DR InterPro; IPR024641; HRS_helical.
DR InterPro; IPR003903; UIM_dom.
DR InterPro; IPR002014; VHS_dom.
DR InterPro; IPR000306; Znf_FYVE.
DR InterPro; IPR017455; Znf_FYVE-rel.
DR InterPro; IPR011011; Znf_FYVE_PHD.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR PANTHER; PTHR46275; PTHR46275; 1.
DR Pfam; PF01363; FYVE; 1.
DR Pfam; PF12210; Hrs_helical; 1.
DR Pfam; PF00790; VHS; 1.
DR PIRSF; PIRSF036956; Hrs_Vps27; 1.
DR SMART; SM00064; FYVE; 1.
DR SMART; SM00288; VHS; 1.
DR SUPFAM; SSF48464; SSF48464; 1.
DR SUPFAM; SSF57903; SSF57903; 1.
DR PROSITE; PS50330; UIM; 1.
DR PROSITE; PS50179; VHS; 1.
DR PROSITE; PS50178; ZF_FYVE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Developmental protein;
KW Metal-binding; Phosphoprotein; Reference proteome; Zinc; Zinc-finger.
FT CHAIN 1..760
FT /note="Hepatocyte growth factor-regulated tyrosine kinase
FT substrate"
FT /id="PRO_0000084070"
FT DOMAIN 13..141
FT /note="VHS"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00218,
FT ECO:0000305"
FT DOMAIN 263..282
FT /note="UIM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00213"
FT ZN_FING 158..218
FT /note="FYVE-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091,
FT ECO:0000305"
FT REGION 275..323
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 338..359
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 602..626
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 644..760
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 602..619
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 657..704
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 164
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 167
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 180
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 183
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 188
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 191
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 210
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 213
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT MOD_RES 300
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:18327897"
FT MOD_RES 302
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:18327897"
FT VAR_SEQ 1..14
FT /note="MFRSSFDKNLENAT -> MSSEEELSIEEESL (in isoform A)"
FT /evidence="ECO:0000305"
FT /id="VSP_029168"
FT VAR_SEQ 15..127
FT /note="Missing (in isoform A)"
FT /evidence="ECO:0000305"
FT /id="VSP_029169"
FT CONFLICT 471
FT /note="E -> G (in Ref. 4; AAN71346)"
FT /evidence="ECO:0000305"
FT HELIX 5..14
FT /evidence="ECO:0007829|PDB:1DVP"
FT HELIX 23..34
FT /evidence="ECO:0007829|PDB:1DVP"
FT HELIX 40..51
FT /evidence="ECO:0007829|PDB:1DVP"
FT HELIX 56..72
FT /evidence="ECO:0007829|PDB:1DVP"
FT HELIX 74..81
FT /evidence="ECO:0007829|PDB:1DVP"
FT HELIX 84..96
FT /evidence="ECO:0007829|PDB:1DVP"
FT HELIX 100..116
FT /evidence="ECO:0007829|PDB:1DVP"
FT TURN 117..119
FT /evidence="ECO:0007829|PDB:1DVP"
FT HELIX 125..135
FT /evidence="ECO:0007829|PDB:1DVP"
FT TURN 165..167
FT /evidence="ECO:0007829|PDB:1DVP"
FT STRAND 173..175
FT /evidence="ECO:0007829|PDB:1DVP"
FT TURN 181..183
FT /evidence="ECO:0007829|PDB:1DVP"
FT STRAND 194..198
FT /evidence="ECO:0007829|PDB:1DVP"
FT HELIX 199..201
FT /evidence="ECO:0007829|PDB:1DVP"
FT STRAND 203..209
FT /evidence="ECO:0007829|PDB:1DVP"
FT HELIX 211..219
FT /evidence="ECO:0007829|PDB:1DVP"
SQ SEQUENCE 760 AA; 85415 MW; 993833378D094F2C CRC64;
MFRSSFDKNL ENATSHLRLE PDWPSILLIC DEINQKDVTP KNAFAAIKKK MNSPNPHSSC
YSLLVLESIV KNCGAPVHEE VFTKENCEMF SSFLESTPHE NVRQKMLELV QTWAYAFRSS
DKYQAIKDTM TILKAKGHTF PELREADAMF TADTAPNWAD GRVCHRCRVE FTFTNRKHHC
RNCGQVFCGQ CTAKQCPLPK YGIEKEVRVC DGCFAALQRP TSGSGGAKSG PRPADSELPA
EYLNSTLAQQ VQTPARKTEQ ELKEEEELQL ALALSQSEAE QQKPKLQSLP PAAYRMQQRS
PSPEAPPEPK EYHQQPEEAT NPELAKYLNR SYWEQRKISE SSSMASPSAP SPMPPTPQPQ
QIMPLQVKSA DEVQIDEFAA NMRTQVEIFV NRMKSNSSRG RSISNDSSVQ TLFMTLTSLH
SQQLSYIKEM DDKRMWYEQL QDKLTQIKDS RAALDQLRQE HVEKLRRIAE EQERQRQMQM
AQKLDIMRKK KQEYLQYQRQ LALQRIQEQE REMQLRQEQQ KAQYLMGQSA PPFPYMPPSA
VPQHGSPSHQ LNNVYNPYAA GVPGYLPQGP APAPNGHGQF QAIPPGMYNP AIQQPMPPNL
QPGGLMQQPA PPGNPQMMPP MPENQFANNP AAILQLPQQH SIAQPPQIPF QPQPQQIPGQ
QPQQIPGQQP QQIPGQQPQQ IPGQQPQQIP VQQPQPQPQM GHVMLQQHQA PPAAQAPPVT
EIANNQVQAV AAAPAPPQNE PGPAPVKAEE PATAELISFD
