Biology:TSG101
![]() Generic protein structure example |
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 TSG101 is to participate in ESCRT pathway. This pathway facilitates reverse topology budding and formation of multivesicular bodies (MVB) which delivers cargo destined for degradation to the lysosomes.[2] TSG101 recognises short linear motif : P(T/S)AP 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.[3][4]
Viral Hijacking
TSG101 plays an important role in the pathogenesis of HIV and other viruses. In uninfected cells, TSG101 functions in the biogenesis of the multivesicular body (MVB),[5] which suggests that HIV may bind TSG101 in order to gain access to the downstream machinery that catalyzes MVB vesicle budding.[6]
Interactions
TSG101 has been shown to interact with:
Orthologue, Vps23
Vps23_core | |||||||||
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Identifiers | |||||||||
Symbol | Vps23_core | ||||||||
Pfam | PF09454 | ||||||||
InterPro | IPR017916 | ||||||||
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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.
See also
References
- ↑ "Entrez Gene: TSG101 tumor susceptibility gene 101". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7251.
- ↑ "The ESCRT pathway". Developmental Cell 21 (1): 77–91. July 2011. doi:10.1016/j.devcel.2011.05.015. PMID 21763610.
- ↑ "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. April 2006. doi:10.1016/j.cell.2006.01.047. PMID 16615893.
- ↑ "Structural and functional organization of the ESCRT-I trafficking complex". Cell 125 (1): 113–26. April 2006. doi:10.1016/j.cell.2006.01.049. PMID 16615894.
- ↑ "Receptor downregulation and multivesicular-body sorting". Nat. Rev. Mol. Cell Biol. 3 (12): 893–905. 2002. doi:10.1038/nrm973. PMID 12461556.
- ↑ "The protein network of HIV budding". Cell 114 (6): 701–13. 2003. doi:10.1016/S0092-8674(03)00714-1. PMID 14505570.
- ↑ "Tumor susceptibility gene 101 protein represses androgen receptor transactivation and interacts with p300". Cancer 86 (4): 689–96. August 1999. doi:10.1002/(sici)1097-0142(19990815)86:4<689::aid-cncr19>3.0.co;2-p. PMID 10440698.
- ↑ 8.0 8.1 8.2 "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. October 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R.
- ↑ "TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation". Proc. Natl. Acad. Sci. U.S.A. 100 (13): 7626–31. June 2003. doi:10.1073/pnas.0932599100. PMID 12802020. Bibcode: 2003PNAS..100.7626L.
- ↑ "Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding". Genes Dev. 18 (14): 1737–52. July 2004. doi:10.1101/gad.294904. PMID 15256501.
- ↑ "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. April 2002. doi:10.1073/pnas.082123999. PMID 11943869. Bibcode: 2002PNAS...99.5430O.
- ↑ "A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control". Proc. Natl. Acad. Sci. U.S.A. 98 (4): 1619–24. February 2001. doi:10.1073/pnas.98.4.1619. PMID 11172000. Bibcode: 2001PNAS...98.1619L.
- ↑ "The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding". J. Biol. Chem. 279 (34): 36059–71. August 2004. doi:10.1074/jbc.M405226200. PMID 15218037.
- ↑ "TSG101/mammalian VPS23 and mammalian VPS28 interact directly and are recruited to VPS4-induced endosomes". J. Biol. Chem. 276 (15): 11735–42. April 2001. doi:10.1074/jbc.M009863200. PMID 11134028.
Further reading
- "The role of viral and cellular proteins in the budding of human immunodeficiency virus.". Acta Virol. 50 (2): 75–85. 2006. PMID 16808324.
- "The cell biology of HIV-1 and other retroviruses.". Retrovirology 3: 77. 2006. doi:10.1186/1742-4690-3-77. PMID 17083721.
- "The TSG101 tumor susceptibility gene is located in chromosome 11 band p15 and is mutated in human breast cancer.". Cell 88 (1): 143–54. 1997. doi:10.1016/S0092-8674(00)81866-8. PMID 9019400.
- "TSG101 may be the prototype of a class of dominant negative ubiquitin regulators.". Nat. Genet. 16 (4): 330–1. 1997. doi:10.1038/ng0897-330. PMID 9241264.
- "Absence of rearrangements in the tumour susceptibility gene TSG101 in human breast cancer.". Nat. Genet. 16 (4): 332–3. 1997. doi:10.1038/ng0897-332. PMID 9241265.
- "Aberrant splicing but not mutations of TSG101 in human breast cancer.". Cancer Res. 57 (15): 3131–4. 1997. PMID 9242438.
- "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. 1997. doi:10.1038/sj.onc.1201591. PMID 9366528.
- "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. 1998. doi:10.1073/pnas.95.4.1595. PMID 9465061. Bibcode: 1998PNAS...95.1595X.
- "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. 1998. doi:10.1038/sj.onc.1202529. PMID 9840940.
- "Tumor susceptibility gene 101 protein represses androgen receptor transactivation and interacts with p300.". Cancer 86 (4): 689–96. 1999. doi:10.1002/(SICI)1097-0142(19990815)86:4<689::AID-CNCR19>3.0.CO;2-P. PMID 10440698.
- "Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins.". EMBO J. 18 (19): 5380–8. 1999. doi:10.1093/emboj/18.19.5380. PMID 10508170.
- "DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci.". Nat. Genet. 25 (3): 269–77. 2000. doi:10.1038/77023. PMID 10888872.
- "TSG101/mammalian VPS23 and mammalian VPS28 interact directly and are recruited to VPS4-induced endosomes.". J. Biol. Chem. 276 (15): 11735–42. 2001. doi:10.1074/jbc.M009863200. PMID 11134028.
- "A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control.". Proc. Natl. Acad. Sci. U.S.A. 98 (4): 1619–24. 2001. doi:10.1073/pnas.98.4.1619. PMID 11172000. Bibcode: 2001PNAS...98.1619L.
- "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. 2001. doi:10.1073/pnas.131059198. PMID 11427703. Bibcode: 2001PNAS...98.7724V.
- "Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding.". Cell 107 (1): 55–65. 2001. doi:10.1016/S0092-8674(01)00506-2. PMID 11595185.
- "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. 2002. doi:10.1038/nm1201-1313. PMID 11726971.
- "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. 2002. doi:10.1073/pnas.032511899. PMID 11805336. Bibcode: 2002PNAS...99..955D.
- "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. 2002. PMID 11838966.
- "Mammalian class E vps proteins recognize ubiquitin and act in the removal of endosomal protein-ubiquitin conjugates.". J. Cell Biol. 157 (1): 91–101. 2002. doi:10.1083/jcb.200112080. PMID 11916981.