TSG101

Tumor susceptibility 101

PDB rendering based on 1kpp.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
1KPP, 1KPQ, 1M4P, 1M4Q, 1S1Q, 2F0R, 3IV1, 3OBQ, 3OBS, 3OBU, 3OBX, 3P9G, 3P9H, 4EJE

Identifiers

Symbols

TSG101 ; TSG10; VPS23

External IDs

OMIM: 601387 MGI: 106581 HomoloGene: 4584 ChEMBL: 6157 GeneCards: TSG101 Gene

Gene ontology
Molecular function	• DNA binding • transcription corepressor activity • protein binding • ligand-dependent nuclear receptor transcription coactivator activity • ubiquitin protein ligase binding • protein homodimerization activity • ubiquitin binding • virion binding • calcium-dependent protein binding
Cellular component	• ESCRT I complex • nucleolus • cytoplasm • endosome • early endosome • late endosome • multivesicular body • plasma membrane • endosome membrane • late endosome membrane • extracellular exosome
Biological process	• regulation of cell growth • protein monoubiquitination • cell cycle arrest • negative regulation of cell proliferation • endosome to lysosome transport • protein transport • viral process • endosomal transport • viral life cycle • virion assembly • viral protein processing • keratinocyte differentiation • ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway • regulation of MAP kinase activity • negative regulation of transcription, DNA-templated • viral budding • positive regulation of viral process • cell division • membrane organization • intracellular transport of virus • regulation of viral release from host cell • positive regulation of viral release from host cell • positive regulation of exosomal secretion • regulation of extracellular exosome assembly • regulation of viral budding via host ESCRT complex • positive regulation of viral budding via host ESCRT complex • positive regulation of ubiquitin-dependent endocytosis
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 11:
18.47 – 18.53 Mb

Chr 7:
46.89 – 46.92 Mb

PubMed search

Tumor susceptibility gene 101, also known as TSG101, is a human gene that encodes for a cellular protein of the same name.

Function

The protein encoded by this gene belongs to a group of apparently inactive homologs of ubiquitin-conjugating enzymes. The gene product contains a coiled-coil domain that interacts with stathmin, a cytosolic phosphoprotein implicated in tumorigenesis. The protein may play a role in cell growth and differentiation and act as a negative growth regulator. In vitro steady-state expression of this tumor susceptibility gene appears to be important for maintenance of genomic stability and cell cycle regulation. Mutations and alternative splicing in this gene occur in high frequency in breast cancer and suggest that defects occur during breast cancer tumorigenesis and/or progression.^[1]

The main role of ESCRT-I is to recognise ubiquitinated cargo via the UEV protein domain of the VPS23/TSG101 subunit. The assembly of the ESCRT-I complex is directed by the C-terminal steadiness box (SB) of VPS23, the N-terminal half of VPS28, and the C-terminal half of VPS37. The structure is primarily composed of three long, parallel helical hairpins, each corresponding to a different subunit. The additional domains and motifs extending beyond the core serve as gripping tools for ESCRT-I critical functions.^[2]^[3]

HIV

TSG101 seems to play an important role in the pathogenesis of HIV. In uninfected cells, TSG101 functions in the biogenesis of the multivesicular body (MVB),^[4] which suggests that HIV may bind TSG101 in order to gain access to the downstream machinery that catalyzes MVB vesicle budding.^[5]

Interactions

TSG101 has been shown to interact with:

Orthologue, Vps23

Vps23_core

escrt-i core

Identifiers

Symbol

Vps23_core

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

In humans, the orthologue of vps23 which has a component of ESCRT-1 is called Tsg101. Mutations in Tsg-101 have been linked to cervical, breast, prostate and gastrointestinal cancers. In molecular biology, vps23 (vacuolar protein sorting) is a protein domain. Vps proteins are components of the ESCRTs (endosomal sorting complexes required for transport) which are required for protein sorting at the early endosome. More specifically, vps23 is a component of ESCRT-I. The ESCRT complexes form the machinery driving protein sorting from endosomes to lysosomes. ESCRT complexes are central to receptor down-regulation, lysosome biogenesis and budding of HIV.

Structure

Yeast ESCRT-I consists of three protein subunits, VPS23, VPS28, and VPS37. In humans, ESCRT-I comprises TSG101, VPS28, and one of four potential human VPS37 homologues.

References

↑ "Entrez Gene: TSG101 tumor susceptibility gene 101".
↑ Teo H, Gill DJ, Sun J, Perisic O, Veprintsev DB, Vallis Y, Emr SD, Williams RL (April 2006). "ESCRT-I core and ESCRT-II GLUE domain structures reveal role for GLUE in linking to ESCRT-I and membranes". Cell 125 (1): 99–111. doi:10.1016/j.cell.2006.01.047. PMID 16615893.
↑ Kostelansky MS, Sun J, Lee S, Kim J, Ghirlando R, Hierro A, Emr SD, Hurley JH (April 2006). "Structural and functional organization of the ESCRT-I trafficking complex". Cell 125 (1): 113–26. doi:10.1016/j.cell.2006.01.049. PMC 1576341. PMID 16615894.
↑ Katzmann DJ, Odorizzi G, Emr SD (2002). "Receptor downregulation and multivesicular-body sorting". Nat. Rev. Mol. Cell Biol. 3 (12): 893–905. doi:10.1038/nrm973. PMID 12461556.
↑ von Schwedler UK, Stuchell M, Müller B, Ward DM, Chung HY, Morita E, Wang HE, Davis T, He GP, Cimbora DM, Scott A, Kräusslich HG, Kaplan J, Morham SG, Sundquist WI (2003). "The protein network of HIV budding". Cell 114 (6): 701–13. doi:10.1016/S0092-8674(03)00714-1. PMID 14505570.
↑ Sun Z, Pan J, Hope WX, Cohen SN, Balk SP (August 1999). "Tumor susceptibility gene 101 protein represses androgen receptor transactivation and interacts with p300". Cancer 86 (4): 689–96. doi:10.1002/(sici)1097-0142(19990815)86:4<689::aid-cncr19>3.0.co;2-p. PMID 10440698.
1 2 3 Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
↑ Lu Q, Hope LW, Brasch M, Reinhard C, Cohen SN (June 2003). "TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation". Proc. Natl. Acad. Sci. U.S.A. 100 (13): 7626–31. doi:10.1073/pnas.0932599100. PMC 164637. PMID 12802020.
↑ Amit I, Yakir L, Katz M, Zwang Y, Marmor MD, Citri A, Shtiegman K, Alroy I, Tuvia S, Reiss Y, Roubini E, Cohen M, Wides R, Bacharach E, Schubert U, Yarden Y (July 2004). "Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding". Genes Dev. 18 (14): 1737–52. doi:10.1101/gad.294904. PMC 478194. PMID 15256501.
↑ Oh H, Mammucari C, Nenci A, Cabodi S, Cohen SN, Dotto GP (April 2002). "Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1)". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5430–5. doi:10.1073/pnas.082123999. PMC 122786. PMID 11943869.
↑ Li L, Liao J, Ruland J, Mak TW, Cohen SN (February 2001). "A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control". Proc. Natl. Acad. Sci. U.S.A. 98 (4): 1619–24. doi:10.1073/pnas.98.4.1619. PMC 29306. PMID 11172000.
↑ Stuchell MD, Garrus JE, Müller B, Stray KM, Ghaffarian S, McKinnon R, Kräusslich HG, Morham SG, Sundquist WI (August 2004). "The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding". J. Biol. Chem. 279 (34): 36059–71. doi:10.1074/jbc.M405226200. PMID 15218037.
↑ Bishop N, Woodman P (April 2001). "TSG101/mammalian VPS23 and mammalian VPS28 interact directly and are recruited to VPS4-induced endosomes". J. Biol. Chem. 276 (15): 11735–42. doi:10.1074/jbc.M009863200. PMID 11134028.

Mazzé FM, Degrève L (2006). "The role of viral and cellular proteins in the budding of human immunodeficiency virus.". Acta Virol. 50 (2): 75–85. PMID 16808324.
Freed EO, Mouland AJ (2006). "The cell biology of HIV-1 and other retroviruses.". Retrovirology 3: 77. doi:10.1186/1742-4690-3-77. PMC 1635732. PMID 17083721.
Li L, Li X, Francke U, Cohen SN (1997). "The TSG101 tumor susceptibility gene is located in chromosome 11 band p15 and is mutated in human breast cancer.". Cell 88 (1): 143–54. doi:10.1016/S0092-8674(00)81866-8. PMID 9019400.
Koonin EV, Abagyan RA (1997). "TSG101 may be the prototype of a class of dominant negative ubiquitin regulators.". Nat. Genet. 16 (4): 330–1. doi:10.1038/ng0897-330. PMID 9241264.
Steiner P, Barnes DM, Harris WH, Weinberg RA (1997). "Absence of rearrangements in the tumour susceptibility gene TSG101 in human breast cancer.". Nat. Genet. 16 (4): 332–3. doi:10.1038/ng0897-332. PMID 9241265.
Lee MP, Feinberg AP (1997). "Aberrant splicing but not mutations of TSG101 in human breast cancer.". Cancer Res. 57 (15): 3131–4. PMID 9242438.
Gayther SA, Barski P, Batley SJ, Li L, de Foy KA, Cohen SN, Ponder BA, Caldas C (1997). "Aberrant splicing of the TSG101 and FHIT genes occurs frequently in multiple malignancies and in normal tissues and mimics alterations previously described in tumours.". Oncogene 15 (17): 2119–26. doi:10.1038/sj.onc.1201591. PMID 9366528.
Xie W, Li L, Cohen SN (1998). "Cell cycle-dependent subcellular localization of the TSG101 protein and mitotic and nuclear abnormalities associated with TSG101 deficiency.". Proc. Natl. Acad. Sci. U.S.A. 95 (4): 1595–600. doi:10.1073/pnas.95.4.1595. PMC 19109. PMID 9465061.
Wagner KU, Dierisseau P, Rucker EB, Robinson GW, Hennighausen L (1998). "Genomic architecture and transcriptional activation of the mouse and human tumor susceptibility gene TSG101: common types of shorter transcripts are true alternative splice variants.". Oncogene 17 (21): 2761–70. doi:10.1038/sj.onc.1202529. PMID 9840940.
Sun Z, Pan J, Hope WX, Cohen SN, Balk SP (1999). "Tumor susceptibility gene 101 protein represses androgen receptor transactivation and interacts with p300.". Cancer 86 (4): 689–96. doi:10.1002/(SICI)1097-0142(19990815)86:4<689::AID-CNCR19>3.0.CO;2-P. PMID 10440698.
Hittelman AB, Burakov D, Iñiguez-Lluhí JA, Freedman LP, Garabedian MJ (1999). "Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins.". EMBO J. 18 (19): 5380–8. doi:10.1093/emboj/18.19.5380. PMC 1171607. PMID 10508170.
Rountree MR, Bachman KE, Baylin SB (2000). "DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci.". Nat. Genet. 25 (3): 269–77. doi:10.1038/77023. PMID 10888872.
Bishop N, Woodman P (2001). "TSG101/mammalian VPS23 and mammalian VPS28 interact directly and are recruited to VPS4-induced endosomes.". J. Biol. Chem. 276 (15): 11735–42. doi:10.1074/jbc.M009863200. PMID 11134028.
Li L, Liao J, Ruland J, Mak TW, Cohen SN (2001). "A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control.". Proc. Natl. Acad. Sci. U.S.A. 98 (4): 1619–24. doi:10.1073/pnas.98.4.1619. PMC 29306. PMID 11172000.
VerPlank L, Bouamr F, LaGrassa TJ, Agresta B, Kikonyogo A, Leis J, Carter CA (2001). "Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55(Gag).". Proc. Natl. Acad. Sci. U.S.A. 98 (14): 7724–9. doi:10.1073/pnas.131059198. PMC 35409. PMID 11427703.
Garrus JE, von Schwedler UK, Pornillos OW, Morham SG, Zavitz KH, Wang HE, Wettstein DA, Stray KM, Côté M, Rich RL, Myszka DG, Sundquist WI (2001). "Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding.". Cell 107 (1): 55–65. doi:10.1016/S0092-8674(01)00506-2. PMID 11595185.
Martin-Serrano J, Zang T, Bieniasz PD (2002). "HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress.". Nat. Med. 7 (12): 1313–9. doi:10.1038/nm1201-1313. PMID 11726971.
Demirov DG, Ono A, Orenstein JM, Freed EO (2002). "Overexpression of the N-terminal domain of TSG101 inhibits HIV-1 budding by blocking late domain function.". Proc. Natl. Acad. Sci. U.S.A. 99 (2): 955–60. doi:10.1073/pnas.032511899. PMC 117412. PMID 11805336.
Bennett NA, Pattillo RA, Lin RS, Hsieh CY, Murphy T, Lyn D (2002). "TSG101 expression in gynecological tumors: relationship to cyclin D1, cyclin E, p53 and p16 proteins.". Cell. Mol. Biol. (Noisy-le-grand) 47 (7): 1187–93. PMID 11838966.
Bishop N, Horman A, Woodman P (2002). "Mammalian class E vps proteins recognize ubiquitin and act in the removal of endosomal protein-ubiquitin conjugates.". J. Cell Biol. 157 (1): 91–101. doi:10.1083/jcb.200112080. PMC 2173266. PMID 11916981.

PDB gallery

1kpp: Structure of the Tsg101 UEV domain

1kpq: Structure of the Tsg101 UEV domain

1m4p: Structure of the Tsg101 UEV domain in complex with a HIV-1 PTAP ""late domain"" peptide, DYANA Ensemble

1m4q: STRUCTURE OF THE TSG101 UEV DOMAIN IN COMPLEX WITH A HIV-1 PTAP ""LATE DOMAIN"" PEPTIDE, CNS ENSEMBLE

1s1q: TSG101(UEV) domain in complex with Ubiquitin

2f0r: Crystallographic structure of human Tsg101 UEV domain

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