TSC1_RAT
ID TSC1_RAT Reviewed; 1163 AA.
AC Q9Z136;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Hamartin;
DE AltName: Full=Tuberous sclerosis 1 protein homolog;
GN Name=Tsc1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND MUTAGENESIS OF HIS-287; VAL-674; ARG-1027
RP AND MET-1106.
RC STRAIN=Long Evans; TISSUE=Kidney;
RX PubMed=10029074;
RA Satake N., Kobayashi T., Kobayashi E., Izumi K., Hino O.;
RT "Isolation and characterization of a rat homologue of the human tuberous
RT sclerosis 1 gene (Tsc1) and analysis of its mutations in rat renal
RT carcinomas.";
RL Cancer Res. 59:849-855(1999).
RN [2]
RP INTERACTION WITH TSC2.
RX PubMed=9809973;
RA Plank T.L., Yeung R.S., Henske E.P.;
RT "Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts
RT with tuberin and appears to be localized to cytoplasmic vesicles.";
RL Cancer Res. 58:4766-4770(1998).
RN [3]
RP FUNCTION.
RX PubMed=16707451; DOI=10.1158/0008-5472.can-05-4510;
RA Jiang X., Yeung R.S.;
RT "Regulation of microtubule-dependent protein transport by the
RT TSC2/mammalian target of rapamycin pathway.";
RL Cancer Res. 66:5258-5269(2006).
CC -!- FUNCTION: In complex with TSC2, inhibits the nutrient-mediated or
CC growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by
CC negatively regulating mTORC1 signaling (By similarity). Implicated as a
CC tumor suppressor. Involved in microtubule-mediated protein transport,
CC but this seems to be due to unregulated mTOR signaling
CC (PubMed:16707451). Acts as a co-chaperone for HSP90AA1 facilitating
CC HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and
CC glucocorticoid receptor NR3C1 (By similarity). Increases ATP binding to
CC HSP90AA1 and inhibits HSP90AA1 ATPase activity (By similarity).
CC Competes with the activating co-chaperone AHSA1 for binding to
CC HSP90AA1, thereby providing a reciprocal regulatory mechanism for
CC chaperoning of client proteins (By similarity). Recruits TSC2 to
CC HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2
CC and ubiquitin ligase HERC1 (By similarity).
CC {ECO:0000250|UniProtKB:Q92574, ECO:0000269|PubMed:16707451}.
CC -!- SUBUNIT: Probably forms a complex composed of chaperones HSP90 and
CC HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and
CC client protein TSC2 (By similarity). Probably forms a complex composed
CC of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and
CC client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not
CC contain co-chaperones STIP1/HOP and PTGES3/p23 (By similarity). Forms a
CC complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit
CC TCS2 to the complex (By similarity). Interacts (via C-terminus) with
CC the closed form of HSP90AA1 (via the middle domain and TPR repeat-
CC binding motif) (By similarity). Interacts with TSC2; the interaction
CC stabilizes TSC2 and prevents TSC2 self-aggregation (PubMed:16707451).
CC Interacts with DOCK7 (By similarity). Interacts with FBXW5 (By
CC similarity). Interacts with TBC1D7 (By similarity). Interacts with
CC WDR45B (By similarity). Interacts with RPAP3 and URI1 (By similarity).
CC {ECO:0000250|UniProtKB:Q92574, ECO:0000269|PubMed:16707451}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q92574}.
CC Membrane {ECO:0000250|UniProtKB:Q92574}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:Q92574}. Note=At steady state found in
CC association with membranes. {ECO:0000250|UniProtKB:Q92574}.
CC -!- TISSUE SPECIFICITY: Highly expressed in brain, spleen and kidney,
CC followed by liver and heart.
CC -!- DOMAIN: The putative coiled-coil domain is necessary for interaction
CC with TSC2. {ECO:0000250|UniProtKB:Q92574}.
CC -!- PTM: Phosphorylation at Ser-505 does not affect interaction with TSC2.
CC {ECO:0000250|UniProtKB:Q92574}.
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DR EMBL; AB011821; BAA75254.1; -; mRNA.
DR RefSeq; NP_068626.1; NM_021854.1.
DR RefSeq; XP_006233905.1; XM_006233843.2.
DR RefSeq; XP_006233906.1; XM_006233844.2.
DR RefSeq; XP_006233907.1; XM_006233845.2.
DR RefSeq; XP_006233908.1; XM_006233846.2.
DR RefSeq; XP_006233909.1; XM_006233847.3.
DR AlphaFoldDB; Q9Z136; -.
DR SMR; Q9Z136; -.
DR BioGRID; 248838; 6.
DR IntAct; Q9Z136; 1.
DR STRING; 10116.ENSRNOP00000016904; -.
DR iPTMnet; Q9Z136; -.
DR PhosphoSitePlus; Q9Z136; -.
DR PaxDb; Q9Z136; -.
DR PRIDE; Q9Z136; -.
DR GeneID; 60445; -.
DR KEGG; rno:60445; -.
DR UCSC; RGD:620124; rat.
DR CTD; 7248; -.
DR RGD; 620124; Tsc1.
DR VEuPathDB; HostDB:ENSRNOG00000011470; -.
DR eggNOG; ENOG502QQPT; Eukaryota.
DR HOGENOM; CLU_011546_0_0_1; -.
DR InParanoid; Q9Z136; -.
DR OMA; NRMASYS; -.
DR OrthoDB; 131264at2759; -.
DR PhylomeDB; Q9Z136; -.
DR TreeFam; TF325466; -.
DR Reactome; R-RNO-1632852; Macroautophagy.
DR Reactome; R-RNO-165181; Inhibition of TSC complex formation by PKB.
DR Reactome; R-RNO-380972; Energy dependent regulation of mTOR by LKB1-AMPK.
DR Reactome; R-RNO-5628897; TP53 Regulates Metabolic Genes.
DR Reactome; R-RNO-8854214; TBC/RABGAPs.
DR PRO; PR:Q9Z136; -.
DR Proteomes; UP000002494; Chromosome 3.
DR Bgee; ENSRNOG00000011470; Expressed in skeletal muscle tissue and 18 other tissues.
DR Genevisible; Q9Z136; RN.
DR GO; GO:0005884; C:actin filament; IEA:Ensembl.
DR GO; GO:0005938; C:cell cortex; ISO:RGD.
DR GO; GO:0042995; C:cell projection; IDA:RGD.
DR GO; GO:0101031; C:chaperone complex; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0005856; C:cytoskeleton; IDA:RGD.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0030426; C:growth cone; IDA:RGD.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:RGD.
DR GO; GO:0030027; C:lamellipodium; ISO:RGD.
DR GO; GO:0005811; C:lipid droplet; IEA:Ensembl.
DR GO; GO:0016020; C:membrane; ISO:RGD.
DR GO; GO:0005634; C:nucleus; IDA:ParkinsonsUK-UCL.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:ParkinsonsUK-UCL.
DR GO; GO:0014069; C:postsynaptic density; ISO:RGD.
DR GO; GO:0032991; C:protein-containing complex; IDA:RGD.
DR GO; GO:0033596; C:TSC1-TSC2 complex; ISO:RGD.
DR GO; GO:0042030; F:ATPase inhibitor activity; ISO:RGD.
DR GO; GO:0051087; F:chaperone binding; ISO:RGD.
DR GO; GO:0032794; F:GTPase activating protein binding; IPI:RGD.
DR GO; GO:0030544; F:Hsp70 protein binding; ISO:RGD.
DR GO; GO:0051879; F:Hsp90 protein binding; ISO:RGD.
DR GO; GO:0047485; F:protein N-terminus binding; IPI:RGD.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:RGD.
DR GO; GO:0090630; P:activation of GTPase activity; ISO:RGD.
DR GO; GO:0002250; P:adaptive immune response; ISO:RGD.
DR GO; GO:0008344; P:adult locomotory behavior; IMP:ParkinsonsUK-UCL.
DR GO; GO:0008306; P:associative learning; ISO:RGD.
DR GO; GO:0055007; P:cardiac muscle cell differentiation; ISO:RGD.
DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl.
DR GO; GO:0030030; P:cell projection organization; ISO:RGD.
DR GO; GO:0007160; P:cell-matrix adhesion; ISO:RGD.
DR GO; GO:0090650; P:cellular response to oxygen-glucose deprivation; IMP:ParkinsonsUK-UCL.
DR GO; GO:0021987; P:cerebral cortex development; ISO:RGD.
DR GO; GO:0046323; P:glucose import; ISO:RGD.
DR GO; GO:0021766; P:hippocampus development; ISO:RGD.
DR GO; GO:0001822; P:kidney development; ISO:RGD.
DR GO; GO:0043379; P:memory T cell differentiation; ISO:RGD.
DR GO; GO:0042552; P:myelination; ISO:RGD.
DR GO; GO:0032780; P:negative regulation of ATP-dependent activity; ISO:RGD.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:RGD.
DR GO; GO:0045792; P:negative regulation of cell size; ISO:RGD.
DR GO; GO:0034260; P:negative regulation of GTPase activity; IMP:RGD.
DR GO; GO:0016242; P:negative regulation of macroautophagy; IMP:ParkinsonsUK-UCL.
DR GO; GO:0010977; P:negative regulation of neuron projection development; IMP:RGD.
DR GO; GO:1903204; P:negative regulation of oxidative stress-induced neuron death; IMP:RGD.
DR GO; GO:0032007; P:negative regulation of TOR signaling; IMP:ParkinsonsUK-UCL.
DR GO; GO:0017148; P:negative regulation of translation; ISO:RGD.
DR GO; GO:0007399; P:nervous system development; ISO:RGD.
DR GO; GO:0001843; P:neural tube closure; ISO:RGD.
DR GO; GO:0051894; P:positive regulation of focal adhesion assembly; ISO:RGD.
DR GO; GO:0016239; P:positive regulation of macroautophagy; IDA:RGD.
DR GO; GO:0051496; P:positive regulation of stress fiber assembly; IMP:RGD.
DR GO; GO:0006813; P:potassium ion transport; ISO:RGD.
DR GO; GO:0050821; P:protein stabilization; ISO:RGD.
DR GO; GO:0051726; P:regulation of cell cycle; IBA:GO_Central.
DR GO; GO:0001952; P:regulation of cell-matrix adhesion; ISO:RGD.
DR GO; GO:0051893; P:regulation of focal adhesion assembly; IMP:RGD.
DR GO; GO:1901214; P:regulation of neuron death; IMP:ParkinsonsUK-UCL.
DR GO; GO:0043666; P:regulation of phosphoprotein phosphatase activity; ISO:RGD.
DR GO; GO:0045859; P:regulation of protein kinase activity; ISO:RGD.
DR GO; GO:0051492; P:regulation of stress fiber assembly; ISO:RGD.
DR GO; GO:0006417; P:regulation of translation; ISO:RGD.
DR GO; GO:0032868; P:response to insulin; ISO:RGD.
DR GO; GO:0031667; P:response to nutrient levels; IEP:RGD.
DR GO; GO:1901652; P:response to peptide; IEP:RGD.
DR GO; GO:0006407; P:rRNA export from nucleus; ISO:RGD.
DR GO; GO:0050808; P:synapse organization; ISO:RGD.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR007483; Hamartin.
DR PANTHER; PTHR15154; PTHR15154; 1.
DR Pfam; PF04388; Hamartin; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
PE 1: Evidence at protein level;
KW Chaperone; Coiled coil; Cytoplasm; Membrane; Phosphoprotein;
KW Reference proteome; Tumor suppressor.
FT CHAIN 1..1163
FT /note="Hamartin"
FT /id="PRO_0000065652"
FT REGION 295..337
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 353..594
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 403..787
FT /note="Mediates interaction with WDR45B"
FT /evidence="ECO:0000250|UniProtKB:Q92574"
FT REGION 1008..1163
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 721..919
FT /evidence="ECO:0000255"
FT COILED 970..994
FT /evidence="ECO:0000255"
FT COMPBIAS 374..389
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 390..404
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 468..484
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 509..534
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 571..585
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1032..1084
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1102..1117
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 487
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92574"
FT MOD_RES 505
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92574"
FT MOD_RES 511
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92574"
FT MOD_RES 521
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92574"
FT MOD_RES 595
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9EP53"
FT MOD_RES 598
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92574"
FT MOD_RES 1097
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92574"
FT MUTAGEN 287
FT /note="H->Q: In chemically induced renal carcinogenesis."
FT /evidence="ECO:0000269|PubMed:10029074"
FT MUTAGEN 674
FT /note="V->L: In chemically induced renal carcinogenesis."
FT /evidence="ECO:0000269|PubMed:10029074"
FT MUTAGEN 1027
FT /note="R->W: In chemically induced renal carcinogenesis."
FT /evidence="ECO:0000269|PubMed:10029074"
FT MUTAGEN 1106
FT /note="M->V: In chemically induced renal carcinogenesis."
FT /evidence="ECO:0000269|PubMed:10029074"
SQ SEQUENCE 1163 AA; 129022 MW; CB5AE6A12AE3B0A1 CRC64;
MAQLANIGEL LSMLDSSTLG VRDDVTTIFK ESLNSERGPM LVNTLVDYYL ETNSQPVLHI
LTTLQEPHDK HLLDKMNEYV GKAATRLSIL SLLGHVVRLQ PSWKHKLSQA PLLPSLLKCL
KMDTDVVVLT TGVLVLITML PMIPQSGKQH LLDFFDIFGR LSSWCLKKPG HVTEVYLVHL
HASVYALFHR LYGMYPCNFV SFLRSHYSMK ENVETFEEVV KPMMEHVRIH PELVTGSKDH
ELDPRRWKTL ETHDVVIECA KISLDPTEAS YEDGDAVSHQ LSACFPHRSA DVTTSSYVDT
QNSYGGATST PSSTSRLMLF STPGQLPQSL SSLSTRPLPE PLQASLWSPS AVCGMTTPPT
SPGNVPADLS HPYSKAFGTT TGGKGTPSGT PATSPPPAPP CPQDDCAHGP ASQASATPPR
KEERADSSRP YLPRQQDVPS DRGLEDLPGS KGSVTLRNLP DFLGDLASEE DSIEKDKEEA
AISKELSEIT TAEADPVAPR GGFDSPFYRD SLSGSQRKTH SAASGTQGFS VNPEPLHSSL
DKHGPDTPKQ AFTPIDPPSG SADASPAGDR DRQTSLETSI LTPSPCKIPP QRGVSFGSGQ
LPPYDHLFEV ALPKTACHFV SKKTEELLKK AKGNPEEDCV PSTSPMEVLD RLLEQGAGAH
SKELSRLSLP SKSVDWTHFG GSPPSDEIRT LRDQLLLLHN QLLYERFKRQ QHALRNRRLL
RKVIRAAALE EHNAAMKDQL KLQEKDIQMW KVSLQKEQAR YSQLQQQRDT MVTQLHSQIR
QLQHDREEFY NQSQELQTKL EDCRSMIAEL RVELKKANSK VCHTELLLSQ VSQKLSNSES
VQQQMEFLNR QLLVLGEVNE LYLEQLQSKH PDTTKEVEMM KTAYRKELEK NRSHLLQQNQ
RLDASQRRVL ELESLLAKKD HLLLEQKKYL EDVKSQASGQ LLAAESRYEA QRKITRVLEL
EILDLYGRLE KDGRLQKLEE DRAEAAEAAE ERLDCCTDGC SDSLLGHNEE AAGHNGETRT
SRPGGTRASC GGRVTGGSSS SSSELSTPEK PPNQRFSSRW EPTMGEPSSS IPTTVGSLPS
SKSFLGMKTR ELFRNKSESQ CDEDGMTMSS FSETLKTELG KDSAGMENKT PPSLDAPHPS
SPSSDSMGQL HIMDYNETHH EHS
