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]
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.
↑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. PMID16615893.
↑ 7.07.17.2Rual 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. PMID16189514.
↑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. PMID15218037.
↑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. PMID11134028.
Further reading
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. PMID16808324.
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. PMID9019400.
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. PMID9241264.
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. PMID9241265.
Lee MP, Feinberg AP (1997). "Aberrant splicing but not mutations of TSG101 in human breast cancer". Cancer Res. 57 (15): 3131–4. PMID9242438.
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. PMID9366528.
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. PMID9840940.
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. PMID10888872.
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. PMID11134028.
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. PMID11595185.
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. PMID11726971.
