CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-008215
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 Tuberin 
Protein Synonyms/Alias
 Tuberous sclerosis 2 protein 
Gene Name
 TSC2 
Gene Synonyms/Alias
 TSC4 
Created Date
 July 27, 2013 
Organism
 Homo sapiens (Human) 
NCBI Taxa ID
 9606 
Lysine Modification
Position
Peptide
Type
References
7*MAKPTSKDSGLKEKubiquitination[1]
14KDSGLKEKFKILLGLubiquitination[1]
16SGLKEKFKILLGLGTubiquitination[1]
34NPRSAEGKQTEFIITubiquitination[1, 2]
69GQICEVAKTKKFEEHubiquitination[1]
71ICEVAKTKKFEEHAVubiquitination[1]
72CEVAKTKKFEEHAVEubiquitination[1, 3, 4]
106HAVLALLKAIVQGQGubiquitination[1, 2]
125VLRALFFKVIKDYPSubiquitination[2]
128ALFFKVIKDYPSNEDubiquitination[1, 2]
144HERLEVFKALTDNGRubiquitination[1, 2, 5]
250LCRTINVKELCEPCWubiquitination[1]
258ELCEPCWKLMRNLLGubiquitination[1]
438AQSIHPAKDGWIQNLubiquitination[1, 2, 3, 4]
634HRLGLPNKDGVVRFSubiquitination[1, 2, 5]
658PERGSEKKTSGPLSPubiquitination[1, 6]
782SYHNYLDKTKQREMVubiquitination[1]
914DFVPFITKGLRSNVLubiquitination[1, 2, 3, 4, 5, 6]
930SFDDTPEKDSFRARSubiquitination[1, 2]
1043SNFTAVPKRSPVGEFubiquitination[1]
1058LLAGGRTKTWLVGNKubiquitination[1]
1106GVHVRQTKEAPAKLEubiquitination[1]
1111QTKEAPAKLESQAGQubiquitination[1]
1168APAAKPEKASAGTRVubiquitination[1]
1180TRVPVQEKTNLAAYVubiquitination[1]
1242LMAAERFKEHRDTALubiquitination[1]
1251HRDTALYKSLSVPAAubiquitination[1]
1262VPAASTAKPPPLPRSubiquitination[1]
1585LGRLIELKDCQPDKVubiquitination[1]
1658NDSGEDFKLGTIKGQubiquitination[1]
1689LVSLQCRKDMEGLVDubiquitination[1]
1701LVDTSVAKIVSDRNLubiquitination[1, 6]
1739PTDIYPSKWIARLRHubiquitination[1, 6]
1775VHPPSHSKAPAQTPAubiquitination[1]
Reference
 [1] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [2] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [3] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [4] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [5] Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.
 Lee KA, Hammerle LP, Andrews PS, Stokes MP, Mustelin T, Silva JC, Black RA, Doedens JR.
 J Biol Chem. 2011 Dec 2;286(48):41530-8. [PMID: 21987572]
 [6] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724] 
Functional Description
 In complex with TSC1, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling. Acts as a GTPase- activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1. Implicated as a tumor suppressor. Involved in microtubule-mediated protein transport, but this seems to be due to unregulated mTOR signaling. Stimulates weakly the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 in vitro. Mutations in TSC2 lead to constitutive activation of RAP1A in tumors. 
Sequence Annotation
 DOMAIN 1531 1758 Rap-GAP.
 REGION 1 400 Required for interaction with TSC1.
 MOD_RES 927 927 Phosphothreonine.
 MOD_RES 939 939 Phosphoserine; by PKB/AKT1.
 MOD_RES 981 981 Phosphoserine.
 MOD_RES 1132 1132 Phosphoserine.
 MOD_RES 1155 1155 Phosphoserine.
 MOD_RES 1330 1330 Phosphothreonine; by AMPK.
 MOD_RES 1337 1337 Phosphoserine.
 MOD_RES 1338 1338 Phosphoserine.
 MOD_RES 1346 1346 Phosphoserine.
 MOD_RES 1364 1364 Phosphoserine (By similarity).
 MOD_RES 1387 1387 Phosphoserine.
 MOD_RES 1411 1411 Phosphoserine.
 MOD_RES 1418 1418 Phosphoserine.
 MOD_RES 1420 1420 Phosphoserine.
 MOD_RES 1448 1448 Phosphoserine; by AMPK.
 MOD_RES 1452 1452 Phosphoserine.
 MOD_RES 1462 1462 Phosphothreonine; by PKB/AKT1.
 MOD_RES 1798 1798 Phosphoserine; by RPS6KA1.  
Keyword
 Alternative splicing; Complete proteome; Cytoplasm; Disease mutation; GTPase activation; Membrane; Phosphoprotein; Polymorphism; Reference proteome; Tumor suppressor; Ubl conjugation. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 1807 AA 
Protein Sequence
MAKPTSKDSG LKEKFKILLG LGTPRPNPRS AEGKQTEFII TAEILRELSM ECGLNNRIRM 60
IGQICEVAKT KKFEEHAVEA LWKAVADLLQ PERPLEARHA VLALLKAIVQ GQGERLGVLR 120
ALFFKVIKDY PSNEDLHERL EVFKALTDNG RHITYLEEEL ADFVLQWMDV GLSSEFLLVL 180
VNLVKFNSCY LDEYIARMVQ MICLLCVRTA SSVDIEVSLQ VLDAVVCYNC LPAESLPLFI 240
VTLCRTINVK ELCEPCWKLM RNLLGTHLGH SAIYNMCHLM EDRAYMEDAP LLRGAVFFVG 300
MALWGAHRLY SLRNSPTSVL PSFYQAMACP NEVVSYEIVL SITRLIKKYR KELQVVAWDI 360
LLNIIERLLQ QLQTLDSPEL RTIVHDLLTT VEELCDQNEF HGSQERYFEL VERCADQRPE 420
SSLLNLISYR AQSIHPAKDG WIQNLQALME RFFRSESRGA VRIKVLDVLS FVLLINRQFY 480
EEELINSVVI SQLSHIPEDK DHQVRKLATQ LLVDLAEGCH THHFNSLLDI IEKVMARSLS 540
PPPELEERDV AAYSASLEDV KTAVLGLLVI LQTKLYTLPA SHATRVYEML VSHIQLHYKH 600
SYTLPIASSI RLQAFDFLLL LRADSLHRLG LPNKDGVVRF SPYCVCDYME PERGSEKKTS 660
GPLSPPTGPP GPAPAGPAVR LGSVPYSLLF RVLLQCLKQE SDWKVLKLVL GRLPESLRYK 720
VLIFTSPCSV DQLCSALCSM LSGPKTLERL RGAPEGFSRT DLHLAVVPVL TALISYHNYL 780
DKTKQREMVY CLEQGLIHRC ASQCVVALSI CSVEMPDIII KALPVLVVKL THISATASMA 840
VPLLEFLSTL ARLPHLYRNF AAEQYASVFA ISLPYTNPSK FNQYIVCLAH HVIAMWFIRC 900
RLPFRKDFVP FITKGLRSNV LLSFDDTPEK DSFRARSTSL NERPKSLRIA RPPKQGLNNS 960
PPVKEFKESS AAEAFRCRSI SVSEHVVRSR IQTSLTSASL GSADENSVAQ ADDSLKNLHL 1020
ELTETCLDMM ARYVFSNFTA VPKRSPVGEF LLAGGRTKTW LVGNKLVTVT TSVGTGTRSL 1080
LGLDSGELQS GPESSSSPGV HVRQTKEAPA KLESQAGQQV SRGARDRVRS MSGGHGLRVG 1140
ALDVPASQFL GSATSPGPRT APAAKPEKAS AGTRVPVQEK TNLAAYVPLL TQGWAEILVR 1200
RPTGNTSWLM SLENPLSPFS SDINNMPLQE LSNALMAAER FKEHRDTALY KSLSVPAAST 1260
AKPPPLPRSN TVASFSSLYQ SSCQGQLHRS VSWADSAVVM EEGSPGEVPV LVEPPGLEDV 1320
EAALGMDRRT DAYSRSSSVS SQEEKSLHAE ELVGRGIPIE RVVSSEGGRP SVDLSFQPSQ 1380
PLSKSSSSPE LQTLQDILGD PGDKADVGRL SPEVKARSQS GTLDGESAAW SASGEDSRGQ 1440
PEGPLPSSSP RSPSGLRPRG YTISDSAPSR RGKRVERDAL KSRATASNAE KVPGINPSFV 1500
FLQLYHSPFF GDESNKPILL PNESQSFERS VQLLDQIPSY DTHKIAVLYV GEGQSNSELA 1560
ILSNEHGSYR YTEFLTGLGR LIELKDCQPD KVYLGGLDVC GEDGQFTYCW HDDIMQAVFH 1620
IATLMPTKDV DKHRCDKKRH LGNDFVSIVY NDSGEDFKLG TIKGQFNFVH VIVTPLDYEC 1680
NLVSLQCRKD MEGLVDTSVA KIVSDRNLPF VARQMALHAN MASQVHHSRS NPTDIYPSKW 1740
IARLRHIKRL RQRICEEAAY SNPSLPLVHP PSHSKAPAQT PAEPTPGYEV GQRKRLISSV 1800
EDFTEFV 1807 
Gene Ontology
 GO:0005901; C:caveola; IEA:Compara.
 GO:0030425; C:dendrite; IEA:Compara.
 GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
 GO:0030426; C:growth cone; IEA:Compara.
 GO:0016020; C:membrane; IDA:UniProtKB.
 GO:0043025; C:neuronal cell body; IEA:Compara.
 GO:0005634; C:nucleus; IDA:UniProtKB.
 GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
 GO:0033596; C:TSC1-TSC2 complex; IDA:UniProtKB.
 GO:0005096; F:GTPase activator activity; IDA:UniProtKB.
 GO:0019902; F:phosphatase binding; IDA:UniProtKB.
 GO:0006953; P:acute-phase response; IEA:Compara.
 GO:0007050; P:cell cycle arrest; TAS:Reactome.
 GO:0030030; P:cell projection organization; IEA:Compara.
 GO:0006897; P:endocytosis; TAS:ProtInc.
 GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
 GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
 GO:0007507; P:heart development; ISS:UniProtKB.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
 GO:0048009; P:insulin-like growth factor receptor signaling pathway; ISS:UniProtKB.
 GO:0008285; P:negative regulation of cell proliferation; ISS:UniProtKB.
 GO:0045792; P:negative regulation of cell size; IBA:RefGenome.
 GO:0050680; P:negative regulation of epithelial cell proliferation; IEA:Compara.
 GO:0043407; P:negative regulation of MAP kinase activity; IEA:Compara.
 GO:0014067; P:negative regulation of phosphatidylinositol 3-kinase cascade; ISS:UniProtKB.
 GO:0006469; P:negative regulation of protein kinase activity; ISS:UniProtKB.
 GO:0051898; P:negative regulation of protein kinase B signaling cascade; ISS:UniProtKB.
 GO:0032007; P:negative regulation of TOR signaling cascade; IBA:RefGenome.
 GO:0030178; P:negative regulation of Wnt receptor signaling pathway; IBA:RefGenome.
 GO:0001843; P:neural tube closure; ISS:UniProtKB.
 GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
 GO:0014065; P:phosphatidylinositol 3-kinase cascade; IEA:Compara.
 GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
 GO:0050918; P:positive chemotaxis; ISS:UniProtKB.
 GO:0051291; P:protein heterooligomerization; IEA:Compara.
 GO:0051260; P:protein homooligomerization; IEA:Compara.
 GO:0006606; P:protein import into nucleus; ISS:UniProtKB.
 GO:0043491; P:protein kinase B signaling cascade; ISS:UniProtKB.
 GO:0030100; P:regulation of endocytosis; ISS:UniProtKB.
 GO:0046626; P:regulation of insulin receptor signaling pathway; ISS:UniProtKB.
 GO:0051056; P:regulation of small GTPase mediated signal transduction; IEA:InterPro.
 GO:0001666; P:response to hypoxia; IEA:Compara. 
Interpro
 IPR011989; ARM-like.
 IPR016024; ARM-type_fold.
 IPR000331; Rap_GAP_dom.
 IPR003913; Tuberin.
 IPR018515; Tuberin-type_domain.
 IPR027107; Tuberin/Ral-act_asu.
 IPR024584; Tuberin_N. 
Pfam
 PF11864; DUF3384
 PF02145; Rap_GAP
 PF03542; Tuberin 
SMART
  
PROSITE
 PS50085; RAPGAP 
PRINTS
 PR01431; TUBERIN.