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KS6B1_RABIT
ID   KS6B1_RABIT             Reviewed;         525 AA.
AC   P67998; P21425;
DT   11-OCT-2004, integrated into UniProtKB/Swiss-Prot.
DT   11-OCT-2004, sequence version 1.
DT   03-AUG-2022, entry version 121.
DE   RecName: Full=Ribosomal protein S6 kinase beta-1;
DE            Short=S6K-beta-1;
DE            Short=S6K1;
DE            EC=2.7.11.1 {ECO:0000250|UniProtKB:P23443};
DE   AltName: Full=70 kDa ribosomal protein S6 kinase 1;
DE            Short=P70S6K1;
DE            Short=p70-S6K 1;
DE   AltName: Full=Ribosomal protein S6 kinase I;
DE   AltName: Full=p70 ribosomal S6 kinase alpha;
DE            Short=p70 S6 kinase alpha;
DE            Short=p70 S6K-alpha;
DE            Short=p70 S6KA;
GN   Name=RPS6KB1;
OS   Oryctolagus cuniculus (Rabbit).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX   NCBI_TaxID=9986;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Liver;
RX   PubMed=1699810; DOI=10.1016/0014-5793(90)81096-7;
RA   Harmann B., Kilimann M.W.;
RT   "cDNA encoding a 59 kDa homolog of ribosomal protein S6 kinase from rabbit
RT   liver.";
RL   FEBS Lett. 273:248-252(1990).
CC   -!- FUNCTION: Serine/threonine-protein kinase that acts downstream of mTOR
CC       signaling in response to growth factors and nutrients to promote cell
CC       proliferation, cell growth and cell cycle progression. Regulates
CC       protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and
CC       contributes to cell survival by repressing the pro-apoptotic function
CC       of BAD. Under conditions of nutrient depletion, the inactive form
CC       associates with the EIF3 translation initiation complex. Upon mitogenic
CC       stimulation, phosphorylation by the mammalian target of rapamycin
CC       complex 1 (mTORC1) leads to dissociation from the EIF3 complex and
CC       activation. The active form then phosphorylates and activates several
CC       substrates in the pre-initiation complex, including the EIF2B complex
CC       and the cap-binding complex component EIF4B. Also controls translation
CC       initiation by phosphorylating a negative regulator of EIF4A, PDCD4,
CC       targeting it for ubiquitination and subsequent proteolysis. Promotes
CC       initiation of the pioneer round of protein synthesis by phosphorylating
CC       POLDIP3/SKAR. In response to IGF1, activates translation elongation by
CC       phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and
CC       thus activation of EEF2. Also plays a role in feedback regulation of
CC       mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition
CC       of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating
CC       the pro-apoptotic protein BAD and suppressing its pro-apoptotic
CC       function. Phosphorylates mitochondrial URI1 leading to dissociation of
CC       a URI1-PPP1CC complex. The free mitochondrial PPP1CC can then
CC       dephosphorylate RPS6KB1 at Thr-412, which is proposed to be a negative
CC       feedback mechanism for the RPS6KB1 anti-apoptotic function. Mediates
CC       TNF-alpha-induced insulin resistance by phosphorylating IRS1 at
CC       multiple serine residues, resulting in accelerated degradation of IRS1.
CC       In cells lacking functional TSC1-2 complex, constitutively
CC       phosphorylates and inhibits GSK3B. May be involved in cytoskeletal
CC       rearrangement through binding to neurabin. Phosphorylates and activates
CC       the pyrimidine biosynthesis enzyme CAD, downstream of MTOR. Following
CC       activation by mTORC1, phosphorylates EPRS and thereby plays a key role
CC       in fatty acid uptake by adipocytes and also most probably in
CC       interferon-gamma-induced translation inhibition.
CC       {ECO:0000250|UniProtKB:P23443}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC         [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000250|UniProtKB:P23443};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC         threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC         Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC         EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:P23443};
CC   -!- ACTIVITY REGULATION: Activation requires multiple phosphorylation
CC       events on serine/threonine residues. Activation appears to be first
CC       mediated by phosphorylation of multiple sites in the autoinhibitory
CC       domain, which facilitates phosphorylation at Thr-412, disrupting the
CC       autoinhibitory mechanism and allowing phosphorylation of Thr-252 by
CC       PDPK1. The active conformation of the kinase is believed to be
CC       stabilized by a mechanism involving three conserved phosphorylation
CC       sites located in the kinase domain activation loop (Thr-252) and in the
CC       AGC-kinase C-terminal domain (Ser-394 in the middle of the tail/linker
CC       region and Thr-412 within a hydrophobic motif at its end). Activated by
CC       mTORC1; isoform Alpha I and isoform Alpha II are sensitive to
CC       rapamycin, which inhibits activating phosphorylation at Thr-412.
CC       Activated by PDPK1 (By similarity). {ECO:0000250}.
CC   -!- SUBUNIT: Interacts with PPP1R9A/neurabin-1. Interacts with RPTOR.
CC       Interacts with IRS1. Interacts with EIF3B and EIF3C. Interacts with
CC       TRAF4. Interacts with POLDIP3. Interacts (via N-terminus) with IER5.
CC       {ECO:0000250|UniProtKB:P23443, ECO:0000250|UniProtKB:P67999}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Synapse, synaptosome
CC       {ECO:0000250}. Mitochondrion outer membrane {ECO:0000250}.
CC       Mitochondrion {ECO:0000250}. Note=Colocalizes with URI1 at
CC       mitochondrion. {ECO:0000250}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative initiation; Named isoforms=2;
CC       Name=Alpha I;
CC         IsoId=P67998-1; Sequence=Displayed;
CC       Name=Alpha II;
CC         IsoId=P67998-2; Sequence=VSP_018841;
CC   -!- DOMAIN: The autoinhibitory domain is believed to block phosphorylation
CC       within the AGC-kinase C-terminal domain and the activation loop.
CC       {ECO:0000250}.
CC   -!- DOMAIN: The TOS (TOR signaling) motif is essential for activation by
CC       mTORC1. {ECO:0000250}.
CC   -!- PTM: Phosphorylation at Thr-412 is regulated by mTORC1. The
CC       phosphorylation at this site is maintained by an agonist-dependent
CC       autophosphorylation mechanism. Activated by phosphorylation at Thr-252
CC       by PDPK1. Dephosphorylation by PPP1CC at Thr-412 in mitochondrion (By
CC       similarity). {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC       protein kinase family. S6 kinase subfamily. {ECO:0000305}.
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DR   EMBL; X54415; CAA38279.1; -; mRNA.
DR   PIR; S12906; S12906.
DR   RefSeq; NP_001095160.1; NM_001101690.1. [P67998-1]
DR   AlphaFoldDB; P67998; -.
DR   SMR; P67998; -.
DR   STRING; 9986.ENSOCUP00000003969; -.
DR   GeneID; 100009260; -.
DR   KEGG; ocu:100009260; -.
DR   CTD; 6198; -.
DR   eggNOG; KOG0598; Eukaryota.
DR   InParanoid; P67998; -.
DR   OrthoDB; 1132245at2759; -.
DR   Proteomes; UP000001811; Unplaced.
DR   GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR   GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR   GO; GO:0043005; C:neuron projection; IEA:UniProtKB-KW.
DR   GO; GO:0045202; C:synapse; IEA:UniProtKB-SubCell.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004672; F:protein kinase activity; ISS:UniProtKB.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0071363; P:cellular response to growth factor stimulus; ISS:UniProtKB.
DR   GO; GO:0044539; P:long-chain fatty acid import into cell; ISS:UniProtKB.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR   GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; ISS:UniProtKB.
DR   GO; GO:0018105; P:peptidyl-serine phosphorylation; ISS:UniProtKB.
DR   GO; GO:0031929; P:TOR signaling; ISS:UniProtKB.
DR   InterPro; IPR000961; AGC-kinase_C.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR017892; Pkinase_C.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR016238; Ribosomal_S6_kinase.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   Pfam; PF00069; Pkinase; 1.
DR   Pfam; PF00433; Pkinase_C; 1.
DR   PIRSF; PIRSF000605; Ribsml_S6_kin_1; 1.
DR   SMART; SM00133; S_TK_X; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; SSF56112; 1.
DR   PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   2: Evidence at transcript level;
KW   Acetylation; Alternative initiation; Apoptosis; ATP-binding; Cytoplasm;
KW   Kinase; Membrane; Mitochondrion; Mitochondrion outer membrane;
KW   Nucleotide-binding; Phosphoprotein; Reference proteome;
KW   Serine/threonine-protein kinase; Synapse; Synaptosome; Transferase.
FT   CHAIN           1..525
FT                   /note="Ribosomal protein S6 kinase beta-1"
FT                   /id="PRO_0000024346"
FT   DOMAIN          91..352
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   DOMAIN          353..423
FT                   /note="AGC-kinase C-terminal"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT   REGION          1..54
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          380..399
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          424..525
FT                   /note="Autoinhibitory domain"
FT   REGION          486..509
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           28..32
FT                   /note="TOS motif"
FT   COMPBIAS        8..26
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        27..48
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        218
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         97..105
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         123
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         252
FT                   /note="Phosphothreonine; by PDPK1"
FT                   /evidence="ECO:0000250|UniProtKB:P23443"
FT   MOD_RES         394
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P23443"
FT   MOD_RES         412
FT                   /note="Phosphothreonine; by MTOR, NEK6 and NEK7"
FT                   /evidence="ECO:0000250|UniProtKB:P67999"
FT   MOD_RES         434
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P67999"
FT   MOD_RES         441
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P23443"
FT   MOD_RES         444
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P23443"
FT   MOD_RES         447
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P23443"
FT   MOD_RES         452
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P23443"
FT   MOD_RES         516
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P67999"
FT   VAR_SEQ         1..23
FT                   /note="Missing (in isoform Alpha II)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_018841"
SQ   SEQUENCE   525 AA;  59109 MW;  013BA13CCDB908D7 CRC64;
     MRRRRRRDGF YPAPDFRDRE AEDMAGVFDI DLDQPEDAGS EDELEEGGQL NESMDHGGVG
     PYELGMEHCE KFEISETSVN RGPEKIRPEC FELLRVLGKG GYGKVFQVRK VTGANTGKIF
     AMKVLKKAMI VRNAKDTAHT KAERNILEEV KHPFIVDLIY AFQTGGKLYL ILEYLSGGEL
     FMQLEREGIF MEDTACFYLA EISMALGHLH QKGIIYRDLK PENIMLNHQG HVKLTDFGLC
     KESIHDGTVT HTFCGTIEYM APEILMRSGH NRAVDWWSLG ALMYDMLTGA PPFTGENRKK
     TIDKILKCKL NLPPYLTQEA RDLLKKLLKR NAASRLGAGP GDAGEVQAHP FFRHINWEEL
     LARKVEPPFK PLLQSEEDVS QFDSKFTRQT PVDSPDDSTL SESANQVFLG FTYVAPSVLE
     SVKEKFSFEP KIRSPRRFIG SPRTPVSPVK FSPGDFWGRG ASASTANPQT PVEYPMETSG
     IEQMDVTTSG EASAPLPIRQ PNSGPYKKQA FPMISKRPEH LRMNL
 
 
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