| Structural highlights
Function
BST2_HUMAN IFN-induced antiviral host restriction factor which efficiently blocks the release of diverse mammalian enveloped viruses by directly tethering nascent virions to the membranes of infected cells. Acts as a direct physical tether, holding virions to the cell membrane and linking virions to each other. The tethered virions can be internalized by endocytosis and subsequently degraded or they can remain on the cell surface. In either case, their spread as cell-free virions is restricted. Its target viruses belong to diverse families, including retroviridae: human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), simian immunodeficiency viruses (SIVs), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), prototype foamy virus (PFV), Mason-Pfizer monkey virus (MPMV), human T-cell leukemia virus type 1 (HTLV-1), Rous sarcoma virus (RSV) and murine leukemia virus (MLV), flavivirideae: hepatitis C virus (HCV), filoviridae: ebola virus (EBOV) and marburg virus (MARV), arenaviridae: lassa virus (LASV) and machupo virus (MACV), herpesviridae: kaposis sarcoma-associated herpesvirus (KSHV), rhabdoviridae: vesicular stomatitis virus (VSV), orthomyxoviridae: influenza A virus, and paramyxoviridae: nipah virus. Can inhibit cell surface proteolytic activity of MMP14 causing decreased activation of MMP15 which results in inhibition of cell growth and migration. Can stimulate signaling by LILRA4/ILT7 and consequently provide negative feedback to the production of IFN by plasmacytoid dendritic cells in response to viral infection. Plays a role in the organization of the subapical actin cytoskeleton in polarized epithelial cells.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
Publication Abstract from PubMed
HIV-1 and other enveloped viruses can be restricted by a host cellular protein called BST2/tetherin that prevents release of budded viruses from the cell surface. Mature BST2 contains a small cytosolic region, a predicted transmembrane helix, and an extracellular domain with a C-terminal GPI anchor. To advance understanding of BST2 function, we have determined a 2.6 A crystal structure of the extracellular domain of the bacterially expressed recombinant human protein, residues 47-152, under reducing conditions. The structure forms a single long helix that associates as a parallel dimeric coiled coil over its C-terminal two-thirds, while the N-terminal third forms an antiparallel four-helix bundle with another dimer, creating a global tetramer. We also report the 3.45 A resolution structure of BST2(51-151) prepared by expression as a secreted protein in HEK293T cells. This oxidized construct forms a dimer in the crystal that is superimposable with the reduced protein over the C-terminal two-thirds of the molecule, and its N terminus suggests pronounced flexibility. Hydrodynamic data demonstrated that BST2 formed a stable tetramer under reducing conditions and a dimer when oxidized to form disulfide bonds. A mutation that selectively disrupted the tetramer (L70D) increased protein expression modestly but only reduced antiviral activity by approximately threefold. Our data raise the possibility that BST2 may function as a tetramer at some stage, such as during trafficking, and strongly support a model in which the primary functional state of BST2 is a parallel disulfide-bound coiled coil that displays flexibility toward its N terminus.
Structural and functional studies on the extracellular domain of BST2/tetherin in reduced and oxidized conformations.,Schubert HL, Zhai Q, Sandrin V, Eckert DM, Garcia-Maya M, Saul L, Sundquist WI, Steiner RA, Hill CP Proc Natl Acad Sci U S A. 2010 Sep 29. PMID:20880831[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Van Damme N, Goff D, Katsura C, Jorgenson RL, Mitchell R, Johnson MC, Stephens EB, Guatelli J. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe. 2008 Apr 17;3(4):245-52. doi: 10.1016/j.chom.2008.03.001. Epub, 2008 Mar 13. PMID:18342597 doi:10.1016/j.chom.2008.03.001
- ↑ Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature. 2008 Jan 24;451(7177):425-30. doi: 10.1038/nature06553. Epub 2008 Jan 16. PMID:18200009 doi:10.1038/nature06553
- ↑ Perez-Caballero D, Zang T, Ebrahimi A, McNatt MW, Gregory DA, Johnson MC, Bieniasz PD. Tetherin inhibits HIV-1 release by directly tethering virions to cells. Cell. 2009 Oct 30;139(3):499-511. doi: 10.1016/j.cell.2009.08.039. PMID:19879838 doi:10.1016/j.cell.2009.08.039
- ↑ Cao W, Bover L, Cho M, Wen X, Hanabuchi S, Bao M, Rosen DB, Wang YH, Shaw JL, Du Q, Li C, Arai N, Yao Z, Lanier LL, Liu YJ. Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction. J Exp Med. 2009 Jul 6;206(7):1603-14. doi: 10.1084/jem.20090547. Epub 2009 Jun, 29. PMID:19564354 doi:10.1084/jem.20090547
- ↑ Jouvenet N, Neil SJ, Zhadina M, Zang T, Kratovac Z, Lee Y, McNatt M, Hatziioannou T, Bieniasz PD. Broad-spectrum inhibition of retroviral and filoviral particle release by tetherin. J Virol. 2009 Feb;83(4):1837-44. doi: 10.1128/JVI.02211-08. Epub 2008 Nov 26. PMID:19036818 doi:10.1128/JVI.02211-08
- ↑ Kaletsky RL, Francica JR, Agrawal-Gamse C, Bates P. Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2886-91. doi:, 10.1073/pnas.0811014106. Epub 2009 Jan 28. PMID:19179289 doi:10.1073/pnas.0811014106
- ↑ Radoshitzky SR, Dong L, Chi X, Clester JC, Retterer C, Spurgers K, Kuhn JH, Sandwick S, Ruthel G, Kota K, Boltz D, Warren T, Kranzusch PJ, Whelan SP, Bavari S. Infectious Lassa virus, but not filoviruses, is restricted by BST-2/tetherin. J Virol. 2010 Oct;84(20):10569-80. doi: 10.1128/JVI.00103-10. Epub 2010 Aug 4. PMID:20686043 doi:10.1128/JVI.00103-10
- ↑ Weidner JM, Jiang D, Pan XB, Chang J, Block TM, Guo JT. Interferon-induced cell membrane proteins, IFITM3 and tetherin, inhibit vesicular stomatitis virus infection via distinct mechanisms. J Virol. 2010 Dec;84(24):12646-57. doi: 10.1128/JVI.01328-10. Epub 2010 Oct 13. PMID:20943977 doi:10.1128/JVI.01328-10
- ↑ Pardieu C, Vigan R, Wilson SJ, Calvi A, Zang T, Bieniasz P, Kellam P, Towers GJ, Neil SJ. The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin. PLoS Pathog. 2010 Apr 15;6(4):e1000843. doi: 10.1371/journal.ppat.1000843. PMID:20419159 doi:10.1371/journal.ppat.1000843
- ↑ Xu F, Tan J, Liu R, Xu D, Li Y, Geng Y, Liang C, Qiao W. Tetherin inhibits prototypic foamy virus release. Virol J. 2011 May 2;8:198. doi: 10.1186/1743-422X-8-198. PMID:21529378 doi:10.1186/1743-422X-8-198
- ↑ Watanabe R, Leser GP, Lamb RA. Influenza virus is not restricted by tetherin whereas influenza VLP production is restricted by tetherin. Virology. 2011 Aug 15;417(1):50-6. doi: 10.1016/j.virol.2011.05.006. Epub 2011, May 28. PMID:21621240 doi:10.1016/j.virol.2011.05.006
- ↑ Gu G, Zhao D, Yin Z, Liu P. BST-2 binding with cellular MT1-MMP blocks cell growth and migration via decreasing MMP2 activity. J Cell Biochem. 2012 Mar;113(3):1013-21. doi: 10.1002/jcb.23433. PMID:22065321 doi:10.1002/jcb.23433
- ↑ Dafa-Berger A, Kuzmina A, Fassler M, Yitzhak-Asraf H, Shemer-Avni Y, Taube R. Modulation of hepatitis C virus release by the interferon-induced protein BST-2/tetherin. Virology. 2012 Jul 5;428(2):98-111. doi: 10.1016/j.virol.2012.03.011. Epub 2012, Apr 20. PMID:22520941 doi:10.1016/j.virol.2012.03.011
- ↑ Hinz A, Miguet N, Natrajan G, Usami Y, Yamanaka H, Renesto P, Hartlieb B, McCarthy AA, Simorre JP, Gottlinger H, Weissenhorn W. Structural basis of HIV-1 tethering to membranes by the BST-2/tetherin ectodomain. Cell Host Microbe. 2010 Apr 22;7(4):314-23. PMID:20399176 doi:10.1016/j.chom.2010.03.005
- ↑ Yang H, Wang J, Jia X, McNatt MW, Zang T, Pan B, Meng W, Wang HW, Bieniasz PD, Xiong Y. Structural insight into the mechanisms of enveloped virus tethering by tetherin. Proc Natl Acad Sci U S A. 2010 Oct 12. PMID:20940320 doi:10.1073/pnas.1011485107
- ↑ Schubert HL, Zhai Q, Sandrin V, Eckert DM, Garcia-Maya M, Saul L, Sundquist WI, Steiner RA, Hill CP. Structural and functional studies on the extracellular domain of BST2/tetherin in reduced and oxidized conformations. Proc Natl Acad Sci U S A. 2010 Sep 29. PMID:20880831 doi:10.1073/pnas.1008206107
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