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RAB12_HUMAN
ID   RAB12_HUMAN             Reviewed;         244 AA.
AC   Q6IQ22; A6NEF5; Q4KMQ3;
DT   09-JAN-2007, integrated into UniProtKB/Swiss-Prot.
DT   09-JAN-2007, sequence version 3.
DT   03-AUG-2022, entry version 162.
DE   RecName: Full=Ras-related protein Rab-12;
GN   Name=RAB12;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16177791; DOI=10.1038/nature03983;
RA   Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D.,
RA   Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA   Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J.,
RA   Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L.,
RA   Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A.,
RA   Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C.,
RA   Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K.,
RA   Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R.,
RA   Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.;
RT   "DNA sequence and analysis of human chromosome 18.";
RL   Nature 437:551-555(2005).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Placenta;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [5]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [6]
RP   ACTIVITY REGULATION.
RX   PubMed=20937701; DOI=10.1083/jcb.201008051;
RA   Yoshimura S., Gerondopoulos A., Linford A., Rigden D.J., Barr F.A.;
RT   "Family-wide characterization of the DENN domain Rab GDP-GTP exchange
RT   factors.";
RL   J. Cell Biol. 191:367-381(2010).
RN   [7]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [8]
RP   INTERACTION WITH RABIF.
RX   PubMed=21194374; DOI=10.1515/bc.2011.022;
RA   Wixler V., Wixler L., Altenfeld A., Ludwig S., Goody R.S., Itzen A.;
RT   "Identification and characterisation of novel Mss4-binding Rab GTPases.";
RL   Biol. Chem. 392:239-248(2011).
RN   [9]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA   Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA   Giglione C.;
RT   "Comparative large-scale characterisation of plant vs. mammal proteins
RT   reveals similar and idiosyncratic N-alpha acetylation features.";
RL   Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN   [10]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA   Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA   Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA   Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT   "N-terminal acetylome analyses and functional insights of the N-terminal
RT   acetyltransferase NatB.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN   [11]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21 AND SER-106, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [12]
RP   INTERACTION WITH LRRK2; GDI1 AND GDI2, PHOSPHORYLATION AT SER-106, AND
RP   MUTAGENESIS OF SER-106.
RX   PubMed=26824392; DOI=10.7554/elife.12813;
RA   Steger M., Tonelli F., Ito G., Davies P., Trost M., Vetter M., Wachter S.,
RA   Lorentzen E., Duddy G., Wilson S., Baptista M.A., Fiske B.K., Fell M.J.,
RA   Morrow J.A., Reith A.D., Alessi D.R., Mann M.;
RT   "Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates
RT   a subset of Rab GTPases.";
RL   Elife 5:0-0(2016).
RN   [13]
RP   INTERACTION WITH GDI1; GDI2; CHM; CHML; RILPL1 AND RILPL2, PHOSPHORYLATION
RP   AT SER-106, AND MUTAGENESIS OF SER-106.
RX   PubMed=29125462; DOI=10.7554/elife.31012;
RA   Steger M., Diez F., Dhekne H.S., Lis P., Nirujogi R.S., Karayel O.,
RA   Tonelli F., Martinez T.N., Lorentzen E., Pfeffer S.R., Alessi D.R.,
RA   Mann M.;
RT   "Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation
RT   establishes a connection to ciliogenesis.";
RL   Elife 6:0-0(2017).
RN   [14]
RP   X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 36-208 IN COMPLEX WITH MAGNESIUM
RP   AND GDP.
RG   Structural genomics consortium (SGC);
RT   "Crystal structure of a predicted human GTPase in complex with GDP.";
RL   Submitted (FEB-2009) to the PDB data bank.
CC   -!- FUNCTION: The small GTPases Rab are key regulators of intracellular
CC       membrane trafficking, from the formation of transport vesicles to their
CC       fusion with membranes. Rabs cycle between an inactive GDP-bound form
CC       and an active GTP-bound form that is able to recruit to membranes
CC       different set of downstream effectors directly responsible for vesicle
CC       formation, movement, tethering and fusion. That Rab may play a role in
CC       protein transport from recycling endosomes to lysosomes regulating, for
CC       instance, the degradation of the transferrin receptor. Involved in
CC       autophagy (By similarity). {ECO:0000250}.
CC   -!- ACTIVITY REGULATION: Rab activation is generally mediated by a guanine
CC       exchange factor (GEF), while inactivation through hydrolysis of bound
CC       GTP is catalyzed by a GTPase activating protein (GAP) (By similarity).
CC       That Rab is activated by DENND3, a guanine exchange factor.
CC       {ECO:0000250, ECO:0000269|PubMed:20937701}.
CC   -!- SUBUNIT: Interacts with RABIF (PubMed:21194374). Interacts with OPTN
CC       (By similarity). Interacts with LRRK2; interaction facilitates
CC       phosphorylation of Ser-106 (PubMed:26824392). Interacts with GDI1,
CC       GDI2, CHM and CHML; these interactions are disrupted by phosphorylation
CC       on Ser-106 (PubMed:26824392, PubMed:29125462). Interacts with RILPL1
CC       and RILPL2; these interactions are dependent on phosphorylation of Ser-
CC       106 (PubMed:26824392, PubMed:29125462). {ECO:0000250|UniProtKB:P35283,
CC       ECO:0000269|PubMed:21194374, ECO:0000269|PubMed:26824392,
CC       ECO:0000269|PubMed:29125462}.
CC   -!- INTERACTION:
CC       Q6IQ22; Q5S007: LRRK2; NbExp=2; IntAct=EBI-4289591, EBI-5323863;
CC   -!- SUBCELLULAR LOCATION: Recycling endosome membrane
CC       {ECO:0000250|UniProtKB:P35283}; Lipid-anchor {ECO:0000305}; Cytoplasmic
CC       side {ECO:0000305}. Lysosome membrane {ECO:0000250|UniProtKB:P35283};
CC       Lipid-anchor {ECO:0000305}; Cytoplasmic side {ECO:0000305}. Golgi
CC       apparatus membrane {ECO:0000250|UniProtKB:P51152}. Cytoplasmic vesicle,
CC       autophagosome {ECO:0000250|UniProtKB:P35283}.
CC   -!- PTM: Phosphorylation of Ser-106 in the switch II region by LRRK2
CC       prevents the association of RAB regulatory proteins, including CHM,
CC       CHML and RAB GDP dissociation inhibitors GDI1 and GDI2.
CC       {ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:29125462}.
CC   -!- SIMILARITY: Belongs to the small GTPase superfamily. Rab family.
CC       {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH71600.2; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
CC       Sequence=AAH98407.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
CC       Sequence=BC050338; Type=Frameshift; Evidence={ECO:0000305};
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DR   EMBL; AP001793; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471113; EAX01616.1; -; Genomic_DNA.
DR   EMBL; BC050338; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; BC071600; AAH71600.2; ALT_SEQ; mRNA.
DR   EMBL; BC098407; AAH98407.1; ALT_SEQ; mRNA.
DR   RefSeq; NP_001020471.2; NM_001025300.2.
DR   PDB; 2IL1; X-ray; 2.10 A; A=36-208.
DR   PDBsum; 2IL1; -.
DR   AlphaFoldDB; Q6IQ22; -.
DR   SMR; Q6IQ22; -.
DR   BioGRID; 128387; 17.
DR   IntAct; Q6IQ22; 11.
DR   STRING; 9606.ENSP00000331748; -.
DR   iPTMnet; Q6IQ22; -.
DR   PhosphoSitePlus; Q6IQ22; -.
DR   BioMuta; RAB12; -.
DR   DMDM; 122064944; -.
DR   EPD; Q6IQ22; -.
DR   jPOST; Q6IQ22; -.
DR   MassIVE; Q6IQ22; -.
DR   MaxQB; Q6IQ22; -.
DR   PaxDb; Q6IQ22; -.
DR   PeptideAtlas; Q6IQ22; -.
DR   PRIDE; Q6IQ22; -.
DR   ProteomicsDB; 66478; -.
DR   Antibodypedia; 41715; 127 antibodies from 23 providers.
DR   DNASU; 201475; -.
DR   GeneID; 201475; -.
DR   KEGG; hsa:201475; -.
DR   UCSC; uc002knp.4; human.
DR   CTD; 201475; -.
DR   DisGeNET; 201475; -.
DR   GeneCards; RAB12; -.
DR   HGNC; HGNC:31332; RAB12.
DR   HPA; ENSG00000206418; Tissue enhanced (skeletal).
DR   MIM; 616448; gene.
DR   neXtProt; NX_Q6IQ22; -.
DR   PharmGKB; PA142671102; -.
DR   VEuPathDB; HostDB:ENSG00000206418; -.
DR   eggNOG; KOG0078; Eukaryota.
DR   eggNOG; KOG0395; Eukaryota.
DR   HOGENOM; CLU_041217_2_1_1; -.
DR   InParanoid; Q6IQ22; -.
DR   OrthoDB; 1149105at2759; -.
DR   PhylomeDB; Q6IQ22; -.
DR   TreeFam; TF314097; -.
DR   PathwayCommons; Q6IQ22; -.
DR   Reactome; R-HSA-8873719; RAB geranylgeranylation.
DR   Reactome; R-HSA-8876198; RAB GEFs exchange GTP for GDP on RABs.
DR   SignaLink; Q6IQ22; -.
DR   SIGNOR; Q6IQ22; -.
DR   BioGRID-ORCS; 201475; 12 hits in 1074 CRISPR screens.
DR   ChiTaRS; RAB12; human.
DR   EvolutionaryTrace; Q6IQ22; -.
DR   GenomeRNAi; 201475; -.
DR   Pharos; Q6IQ22; Tbio.
DR   PRO; PR:Q6IQ22; -.
DR   Proteomes; UP000005640; Chromosome 18.
DR   RNAct; Q6IQ22; protein.
DR   Genevisible; Q6IQ22; HS.
DR   GO; GO:0005776; C:autophagosome; IEA:UniProtKB-SubCell.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005768; C:endosome; IBA:GO_Central.
DR   GO; GO:0005794; C:Golgi apparatus; IBA:GO_Central.
DR   GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0032593; C:insulin-responsive compartment; IBA:GO_Central.
DR   GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR   GO; GO:0005765; C:lysosomal membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR   GO; GO:0055037; C:recycling endosome; IBA:GO_Central.
DR   GO; GO:0055038; C:recycling endosome membrane; ISS:UniProtKB.
DR   GO; GO:0008021; C:synaptic vesicle; IBA:GO_Central.
DR   GO; GO:0019003; F:GDP binding; IDA:UniProtKB.
DR   GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR   GO; GO:0003924; F:GTPase activity; IBA:GO_Central.
DR   GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR   GO; GO:0032869; P:cellular response to insulin stimulus; IBA:GO_Central.
DR   GO; GO:0008333; P:endosome to lysosome transport; ISS:UniProtKB.
DR   GO; GO:0030163; P:protein catabolic process; ISS:UniProtKB.
DR   GO; GO:0072659; P:protein localization to plasma membrane; IBA:GO_Central.
DR   GO; GO:0009306; P:protein secretion; IBA:GO_Central.
DR   GO; GO:0032482; P:Rab protein signal transduction; IEA:InterPro.
DR   GO; GO:0017157; P:regulation of exocytosis; IBA:GO_Central.
DR   GO; GO:0006904; P:vesicle docking involved in exocytosis; IBA:GO_Central.
DR   CDD; cd04120; Rab12; 1.
DR   Gene3D; 3.40.50.300; -; 1.
DR   InterPro; IPR027417; P-loop_NTPase.
DR   InterPro; IPR041830; Rab12.
DR   InterPro; IPR005225; Small_GTP-bd_dom.
DR   InterPro; IPR001806; Small_GTPase.
DR   Pfam; PF00071; Ras; 1.
DR   SMART; SM00174; RHO; 1.
DR   SUPFAM; SSF52540; SSF52540; 1.
DR   TIGRFAMs; TIGR00231; small_GTP; 1.
DR   PROSITE; PS51419; RAB; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Autophagy; Cytoplasmic vesicle; Endosome;
KW   Golgi apparatus; GTP-binding; Lipoprotein; Lysosome; Membrane;
KW   Nucleotide-binding; Phosphoprotein; Prenylation; Protein transport;
KW   Reference proteome; Transport.
FT   CHAIN           1..244
FT                   /note="Ras-related protein Rab-12"
FT                   /id="PRO_0000271377"
FT   REGION          1..37
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          225..244
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           71..79
FT                   /note="Effector region"
FT                   /evidence="ECO:0000250"
FT   BINDING         49..57
FT                   /ligand="GTP"
FT                   /ligand_id="ChEBI:CHEBI:37565"
FT   BINDING         97..101
FT                   /ligand="GTP"
FT                   /ligand_id="ChEBI:CHEBI:37565"
FT                   /evidence="ECO:0000250"
FT   BINDING         155..159
FT                   /ligand="GTP"
FT                   /ligand_id="ChEBI:CHEBI:37565"
FT   BINDING         187..188
FT                   /ligand="GTP"
FT                   /ligand_id="ChEBI:CHEBI:37565"
FT   MOD_RES         1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0007744|PubMed:22223895,
FT                   ECO:0007744|PubMed:22814378"
FT   MOD_RES         21
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         25
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P35283"
FT   MOD_RES         106
FT                   /note="Phosphoserine; by LRRK2"
FT                   /evidence="ECO:0000269|PubMed:26824392,
FT                   ECO:0000269|PubMed:29125462, ECO:0007744|PubMed:23186163"
FT   LIPID           243
FT                   /note="S-geranylgeranyl cysteine"
FT                   /evidence="ECO:0000250"
FT   LIPID           244
FT                   /note="S-geranylgeranyl cysteine"
FT                   /evidence="ECO:0000250"
FT   MUTAGEN         106
FT                   /note="S->A: Loss of phosphorylation. No effect on GDI1 and
FT                   GDI2 binding."
FT                   /evidence="ECO:0000269|PubMed:26824392,
FT                   ECO:0000269|PubMed:29125462"
FT   MUTAGEN         106
FT                   /note="S->E: Phosphomimetic mutant. Loss of GDI1, GDI2, CHM
FT                   and CHML binding."
FT                   /evidence="ECO:0000269|PubMed:26824392,
FT                   ECO:0000269|PubMed:29125462"
FT   STRAND          40..48
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   HELIX           55..62
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   STRAND          77..86
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   STRAND          89..98
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   HELIX           102..104
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   HELIX           105..114
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   STRAND          116..123
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   HELIX           127..131
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   HELIX           133..143
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   STRAND          149..155
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   HELIX           157..162
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   HELIX           167..175
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   STRAND          181..184
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   TURN            187..190
FT                   /evidence="ECO:0007829|PDB:2IL1"
FT   HELIX           193..206
FT                   /evidence="ECO:0007829|PDB:2IL1"
SQ   SEQUENCE   244 AA;  27248 MW;  B4DC65DD0DCB45C4 CRC64;
     MDPGAALQRR AGGGGGLGAG SPALSGGQGR RRKQPPRPAD FKLQVIIIGS RGVGKTSLME
     RFTDDTFCEA CKSTVGVDFK IKTVELRGKK IRLQIWDTAG QERFNSITSA YYRSAKGIIL
     VYDITKKETF DDLPKWMKMI DKYASEDAEL LLVGNKLDCE TDREITRQQG EKFAQQITGM
     RFCEASAKDN FNVDEIFLKL VDDILKKMPL DILRNELSNS ILSLQPEPEI PPELPPPRPH
     VRCC
 
 
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