HS90A_RABIT
ID HS90A_RABIT Reviewed; 694 AA.
AC P30946;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 28-JUN-2011, sequence version 2.
DT 03-AUG-2022, entry version 141.
DE RecName: Full=Heat shock protein HSP 90-alpha;
DE EC=3.6.4.10 {ECO:0000250|UniProtKB:P07900};
GN Name=HSP90AA1; Synonyms=HSPCA;
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 PROTEIN SEQUENCE OF 2-41, AND PHOSPHORYLATION AT THR-5 AND THR-7 BY PRKDC.
RX PubMed=2507541; DOI=10.1016/s0021-9258(18)71488-9;
RA Lees-Miller S.P., Anderson C.W.;
RT "The human double-stranded DNA-activated protein kinase phosphorylates the
RT 90-kDa heat-shock protein, hsp90 alpha at two NH2-terminal threonine
RT residues.";
RL J. Biol. Chem. 264:17275-17280(1989).
RN [2]
RP IDENTIFICATION IN A COMPLEX WITH NR3C1 AND FKBP4; PPID; PPP5C OR STIP1.
RX PubMed=9195923; DOI=10.1074/jbc.272.26.16224;
RA Silverstein A.M., Galigniana M.D., Chen M.S., Owens-Grillo J.K.,
RA Chinkers M., Pratt W.B.;
RT "Protein phosphatase 5 is a major component of glucocorticoid
RT receptor.hsp90 complexes with properties of an FK506-binding
RT immunophilin.";
RL J. Biol. Chem. 272:16224-16230(1997).
CC -!- FUNCTION: Molecular chaperone that promotes the maturation, structural
CC maintenance and proper regulation of specific target proteins involved
CC for instance in cell cycle control and signal transduction. Undergoes a
CC functional cycle that is linked to its ATPase activity which is
CC essential for its chaperone activity. This cycle probably induces
CC conformational changes in the client proteins, thereby causing their
CC activation. Interacts dynamically with various co-chaperones that
CC modulate its substrate recognition, ATPase cycle and chaperone
CC function. Engages with a range of client protein classes via its
CC interaction with various co-chaperone proteins or complexes, that act
CC as adapters, simultaneously able to interact with the specific client
CC and the central chaperone itself. Recruitment of ATP and co-chaperone
CC followed by client protein forms a functional chaperone. After the
CC completion of the chaperoning process, properly folded client protein
CC and co-chaperone leave HSP90 in an ADP-bound partially open
CC conformation and finally, ADP is released from HSP90 which acquires an
CC open conformation for the next cycle. Plays a critical role in
CC mitochondrial import, delivers preproteins to the mitochondrial import
CC receptor TOMM70. Apart from its chaperone activity, it also plays a
CC role in the regulation of the transcription machinery. HSP90 and its
CC co-chaperones modulate transcription at least at three different
CC levels. In the first place, they alter the steady-state levels of
CC certain transcription factors in response to various physiological
CC cues. Second, they modulate the activity of certain epigenetic
CC modifiers, such as histone deacetylases or DNA methyl transferases, and
CC thereby respond to the change in the environment. Third, they
CC participate in the eviction of histones from the promoter region of
CC certain genes and thereby turn on gene expression. Binds bacterial
CC lipopolysaccharide (LPS) and mediates LPS-induced inflammatory
CC response, including TNF secretion by monocytes. Antagonizes STUB1-
CC mediated inhibition of TGF-beta signaling via inhibition of STUB1-
CC mediated SMAD3 ubiquitination and degradation. Mediates the association
CC of TOMM70 with IRF3 or TBK1 in mitochondrial outer membrane which
CC promotes host antiviral response. {ECO:0000250|UniProtKB:P07900}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.10;
CC Evidence={ECO:0000250|UniProtKB:P07900};
CC -!- ACTIVITY REGULATION: In the resting state, through the dimerization of
CC its C-terminal domain, HSP90 forms a homodimer which is defined as the
CC open conformation. Upon ATP-binding, the N-terminal domain undergoes
CC significant conformational changes and comes in contact to form an
CC active closed conformation. After HSP90 finishes its chaperoning tasks
CC of assisting the proper folding, stabilization and activation of client
CC proteins under the active state, ATP molecule is hydrolyzed to ADP
CC which then dissociates from HSP90 and directs the protein back to the
CC resting state. Co-chaperone TSC1 promotes ATP binding and inhibits
CC HSP90AA1 ATPase activity. Binding to phosphorylated AHSA1 promotes
CC HSP90AA1 ATPase activity. Inhibited by geldanamycin, Ganetespib (STA-
CC 9090) and SNX-2112. {ECO:0000250|UniProtKB:P07900}.
CC -!- SUBUNIT: Homodimer (By similarity). Identified in NR3C1/GCR steroid
CC receptor-chaperone complexes formed at least by NR3C1, HSP90AA1 and a
CC variety of proteins containing TPR repeats such as FKBP4, FKBP5, PPID,
CC PPP5C or STIP1 (PubMed:9195923). Forms a complex containing HSP90AA1,
CC TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex (By
CC similarity). The closed form interacts (via the middle domain and TPR
CC repeat-binding motif) with co-chaperone TSC1 (via C-terminus) (By
CC similarity). Interacts with TOM34 (By similarity). Interacts with TERT;
CC the interaction, together with PTGES3, is required for correct assembly
CC and stabilization of the TERT holoenzyme complex (By similarity).
CC Interacts with CHORDC1 and DNAJC7 (By similarity). Interacts with STUB1
CC and UBE2N; may couple the chaperone and ubiquitination systems (By
CC similarity). Interacts (via TPR repeat-binding motif) with PPP5C (via
CC TPR repeats); the interaction is direct and activates PPP5C phosphatase
CC activity (By similarity). Following LPS binding, may form a complex
CC with CXCR4, GDF5 and HSPA8 (By similarity). Interacts with KSR1 (By
CC similarity). Interacts with co-chaperone CDC37 (via C-terminus); the
CC interaction inhibits HSP90AA1 ATPase activity (By similarity). May
CC interact with NWD1 (By similarity). Interacts with FNIP1 and FNIP2; the
CC interaction inhibits HSP90AA1 ATPase activity (By similarity).
CC Interacts with co-chaperone AHSA1 (phosphorylated on 'Tyr-223'); the
CC interaction activates HSP90AA1 ATPase activity and results in the
CC dissociation of TSC1 from HSP90AA1 (By similarity). Interacts with FLCN
CC in the presence of FNIP1 (By similarity). Interacts with HSP70, STIP1
CC and PTGES3 (By similarity). Interacts with SMYD3; this interaction
CC enhances SMYD3 histone-lysine N-methyltransferase. Interacts with SGTA
CC (via TPR repeats) (By similarity). Interacts with TTC1 (via TPR
CC repeats) (By similarity). Interacts with HSF1 in an ATP-dependent
CC manner (By similarity). Interacts with MET; the interaction suppresses
CC MET kinase activity (By similarity). Interacts with ERBB2 in an ATP-
CC dependent manner; the interaction suppresses ERBB2 kinase activity (By
CC similarity). Interacts with HIF1A, KEAP1 and RHOBTB2 (By similarity).
CC Interacts with HIF1A, KEAP1 and RHOBTB2 (By similarity). Interacts with
CC HSF1; this interaction is decreased in a IER5-dependent manner,
CC promoting HSF1 accumulation in the nucleus, homotrimerization and DNA-
CC binding activities (By similarity). Interacts with STUB1 and SMAD3 (By
CC similarity). Interacts with HSP90AB1; interaction is constitutive (By
CC similarity). Interacts with HECTD1 (via N-terminus) (By similarity).
CC Interacts with NR3C1 (via domain NR LBD) and NR1D1 (via domain NR LBD)
CC (By similarity). Interacts with NLPR12. Interacts with PDCL3 (By
CC similarity). Interacts with TOMM70; the interaction is required for
CC preprotein mitochondrial import. Interacts with TOMM70, IRF3 and TBK1;
CC the interactions are direct and mediate the association of TOMM70 with
CC IRF3 and TBK1 (By similarity). Forms a complex with ASL, ASS1 and NOS2;
CC the complex regulates cell-autonomous L-arginine synthesis and
CC citrulline recycling while channeling extracellular L-arginine to
CC nitric oxide synthesis pathway. {ECO:0000250|UniProtKB:P07900,
CC ECO:0000250|UniProtKB:P07901, ECO:0000250|UniProtKB:P82995,
CC ECO:0000269|PubMed:9195923}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:P07901}. Cytoplasm
CC {ECO:0000250|UniProtKB:P07901}. Melanosome
CC {ECO:0000250|UniProtKB:P07900}. Cell membrane
CC {ECO:0000250|UniProtKB:P07900}. Mitochondrion
CC {ECO:0000250|UniProtKB:P07900}.
CC -!- DOMAIN: The TPR repeat-binding motif mediates interaction with TPR
CC repeat-containing proteins like the co-chaperone STUB1.
CC {ECO:0000250|UniProtKB:P07900}.
CC -!- PTM: ISGylated. {ECO:0000250|UniProtKB:P07900}.
CC -!- PTM: S-nitrosylated; negatively regulates the ATPase activity and the
CC activation of eNOS by HSP90AA1. {ECO:0000250|UniProtKB:P07900}.
CC -!- PTM: Ubiquitinated via 'Lys-63'-linked polyubiquitination by HECTD1.
CC Ubiquitination promotes translocation into the cytoplasm away from the
CC membrane and secretory pathways. {ECO:0000250|UniProtKB:P07901}.
CC -!- SIMILARITY: Belongs to the heat shock protein 90 family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR PIR; A34461; A34461.
DR AlphaFoldDB; P30946; -.
DR BMRB; P30946; -.
DR SMR; P30946; -.
DR STRING; 9986.ENSOCUP00000001106; -.
DR iPTMnet; P30946; -.
DR eggNOG; KOG0019; Eukaryota.
DR InParanoid; P30946; -.
DR TreeFam; TF300686; -.
DR Proteomes; UP000001811; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:AgBase.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:AgBase.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0016887; F:ATP hydrolysis activity; IEA:InterPro.
DR GO; GO:0051219; F:phosphoprotein binding; IPI:AgBase.
DR GO; GO:0051082; F:unfolded protein binding; IEA:InterPro.
DR GO; GO:0002218; P:activation of innate immune response; ISS:UniProtKB.
DR GO; GO:0098586; P:cellular response to virus; ISS:UniProtKB.
DR GO; GO:0002230; P:positive regulation of defense response to virus by host; ISS:UniProtKB.
DR GO; GO:0032728; P:positive regulation of interferon-beta production; ISS:UniProtKB.
DR GO; GO:0006457; P:protein folding; IEA:InterPro.
DR GO; GO:0042981; P:regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0046677; P:response to antibiotic; ISS:AgBase.
DR GO; GO:0009409; P:response to cold; ISS:AgBase.
DR GO; GO:0009408; P:response to heat; ISS:AgBase.
DR Gene3D; 1.20.120.790; -; 1.
DR Gene3D; 3.30.565.10; -; 1.
DR HAMAP; MF_00505; HSP90; 1.
DR InterPro; IPR003594; HATPase_C.
DR InterPro; IPR036890; HATPase_C_sf.
DR InterPro; IPR019805; Heat_shock_protein_90_CS.
DR InterPro; IPR037196; HSP90_C.
DR InterPro; IPR001404; Hsp90_fam.
DR InterPro; IPR020575; Hsp90_N.
DR InterPro; IPR020568; Ribosomal_S5_D2-typ_fold.
DR PANTHER; PTHR11528; PTHR11528; 1.
DR Pfam; PF02518; HATPase_c; 1.
DR Pfam; PF00183; HSP90; 1.
DR PIRSF; PIRSF002583; Hsp90; 1.
DR PRINTS; PR00775; HEATSHOCK90.
DR SMART; SM00387; HATPase_c; 1.
DR SUPFAM; SSF110942; SSF110942; 1.
DR SUPFAM; SSF54211; SSF54211; 1.
DR SUPFAM; SSF55874; SSF55874; 1.
DR PROSITE; PS00298; HSP90; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Cell membrane; Chaperone; Cytoplasm;
KW Direct protein sequencing; Hydrolase; Membrane; Mitochondrion;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW S-nitrosylation; Stress response; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT CHAIN 2..694
FT /note="Heat shock protein HSP 90-alpha"
FT /evidence="ECO:0000250"
FT /id="PRO_0000409818"
FT REGION 9..236
FT /note="Interaction with NR3C1"
FT /evidence="ECO:0000250|UniProtKB:P07901"
FT REGION 228..275
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 258..578
FT /note="Interaction with NR3C1"
FT /evidence="ECO:0000250|UniProtKB:P07901"
FT REGION 261..694
FT /note="Interaction with FLCN and FNIP1"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT REGION 261..582
FT /note="Interaction with FNIP2 and TSC1"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT REGION 590..693
FT /note="Interaction with NR1D1"
FT /evidence="ECO:0000250|UniProtKB:P07901"
FT REGION 644..694
FT /note="Required for homodimerization"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT REGION 662..694
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 690..694
FT /note="Essential for interaction with SMYD3, TSC1 and
FT STIP1/HOP"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT REGION 691..694
FT /note="Essential for interaction with SGTA and TTC1"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT MOTIF 685..694
FT /note="TPR repeat-binding"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT COMPBIAS 228..243
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 244..260
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 51
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 93
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 112
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 138
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 376
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT MOD_RES 5
FT /note="Phosphothreonine; by PRKDC"
FT /evidence="ECO:0000269|PubMed:2507541"
FT MOD_RES 7
FT /note="Phosphothreonine; by PRKDC"
FT /evidence="ECO:0000269|PubMed:2507541"
FT MOD_RES 58
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P07901"
FT MOD_RES 84
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P07901"
FT MOD_RES 231
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT MOD_RES 249
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT MOD_RES 289
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P07901"
FT MOD_RES 419
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT MOD_RES 429
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P82995"
FT MOD_RES 434
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT MOD_RES 452
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT MOD_RES 465
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT MOD_RES 468
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P07901"
FT MOD_RES 547
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT MOD_RES 560
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:P07900"
FT MOD_RES 603
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P07900"
SQ SEQUENCE 694 AA; 79733 MW; B080801B6C141D05 CRC64;
MPEETQTQDQ PMEEEEVETF AFQAEIAQLM SLIINTFYSN KEIFLRELIS NSSDALDKIR
YESLTDPSKL DSGKELHINL IPNKQDRTLT IVDTGIGMTK ADLINNLGTI AKSGTKAFME
ALQAGADISM IGQFGVGFYS AYLVAEKVTV ITKHNDDEQY AWESSAGGSF TVRTDAGEPM
GRGTKVVLHL KEDQTEYLEE RRIKEIVKKH SQFIGYPITL FVEKERDKEV SDDEAKQPDD
KPEIEDVGSD EEEEEKKDGD IDQEELNKTK PIWTRNPDDI TNEEYGEFYK SLTNDWEDHL
AVKHFSVEGQ LEFRALLFVP RRAPFDLFEN RKKKNNIKLY VRRVFIMDNC EELIPEYLNF
IRGVVDSEDL PLNISREMLQ QSKILKVIRK NLVKKCLELF TELAEDKENY KKFYEQFSKN
IKLGIHEDSQ NRKKLSELLR YYTSASGDEM VSLKDYCTRM KENQKHIYYI TGETKDQVAN
SAFVERLRKH GLEVIYMIEP IDEYCVQQLK EFEGKTLVSV TKEGLELTKF ENLCKIMKDI
LEKKVEKVVV SNRLVTSPCC IVTSTYGWTA NMERIMKAQA LRDNSTMGYM AAKKHLEVNP
DHSIIETLRQ KAEADKNDKS VKDLVILLYE TALLSSGFSL EDPQTHANRI YRMIKLGLGI
DEDDPTADDT AAAVTEEMPP LEGDDDTSRM EEVD
