Structural highlights
Function
[RSAD2_MOUSE] Interferon-inducible iron-sulfur (4FE-4S) cluster-binding antiviral protein which plays a major role in the cell antiviral state induced by type I and type II interferon. Can inhibit a wide range of viruses, including west Nile virus (WNV), dengue virus, sindbis virus, influenza A virus, sendai virus and vesicular stomatitis virus (VSV). Displays antiviral activity against influenza A virus by inhibiting the budding of the virus from the plasma membrane by disturbing the lipid rafts. This is accomplished, at least in part, through binding and inhibition of the enzyme farnesyl diphosphate synthase (FPPS), which is essential for the biosynthesis of isoprenoid-derived lipids. Promotes TLR7 and TLR9-dependent production of IFN-beta production in plasmacytoid dendritic cells (pDCs) by facilitating Lys-63'-linked ubiquitination of IRAK1. Plays a role in CD4+ T-cells activation and differentiation. Facilitates T-cell receptor (TCR)-mediated GATA3 activation and optimal T-helper 2 (Th2) cytokine production by modulating NFKB1 and JUNB activities. Can inhibit secretion of soluble proteins.[1] [2] [3] [4]
Publication Abstract from PubMed
Viperin is a radical S-adenosylmethionine (SAM) enzyme that inhibits viral replication by converting cytidine triphosphate (CTP) into 3'-deoxy-3',4'-didehydro-CTP and by additional undefined mechanisms operating through its N- and C-terminal domains. Here, we describe crystal structures of viperin bound to a SAM analogue and CTP or uridine triphosphate (UTP) and report kinetic parameters for viperin-catalyzed reactions with CTP or UTP as substrates. Viperin orients the C4' hydrogen atom of CTP and UTP similarly for abstraction by a 5'-deoxyadenosyl radical, but the uracil moiety introduces unfavorable interactions that prevent tight binding of UTP. Consistently, kcat is similar for CTP and UTP whereas the Km for UTP is much greater. The structures also show that nucleotide binding results in ordering of the C-terminal tail and reveal that this region contains a P-loop that binds the gamma-phosphate of the bound nucleotide. Collectively, the results explain the selectivity for CTP and reveal a structural role for the C-terminal tail in binding CTP and UTP.
Structural Basis of the Substrate Selectivity of Viperin.,Fenwick MK, Su D, Dong M, Lin H, Ealick SE Biochemistry. 2020 Jan 16. doi: 10.1021/acs.biochem.9b00741. PMID:31917549[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhang Y, Burke CW, Ryman KD, Klimstra WB. Identification and characterization of interferon-induced proteins that inhibit alphavirus replication. J Virol. 2007 Oct;81(20):11246-55. Epub 2007 Aug 8. PMID:17686841 doi:http://dx.doi.org/JVI.01282-07
- ↑ Qiu LQ, Cresswell P, Chin KC. Viperin is required for optimal Th2 responses and T-cell receptor-mediated activation of NF-kappaB and AP-1. Blood. 2009 Apr 9;113(15):3520-9. doi: 10.1182/blood-2008-07-171942. Epub 2008, Dec 1. PMID:19047684 doi:http://dx.doi.org/10.1182/blood-2008-07-171942
- ↑ Saitoh T, Satoh T, Yamamoto N, Uematsu S, Takeuchi O, Kawai T, Akira S. Antiviral protein Viperin promotes Toll-like receptor 7- and Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells. Immunity. 2011 Mar 25;34(3):352-63. doi: 10.1016/j.immuni.2011.03.010. PMID:21435586 doi:http://dx.doi.org/10.1016/j.immuni.2011.03.010
- ↑ Szretter KJ, Brien JD, Thackray LB, Virgin HW, Cresswell P, Diamond MS. The interferon-inducible gene viperin restricts West Nile virus pathogenesis. J Virol. 2011 Nov;85(22):11557-66. doi: 10.1128/JVI.05519-11. Epub 2011 Aug 31. PMID:21880757 doi:http://dx.doi.org/10.1128/JVI.05519-11
- ↑ Fenwick MK, Su D, Dong M, Lin H, Ealick SE. Structural Basis of the Substrate Selectivity of Viperin. Biochemistry. 2020 Jan 16. doi: 10.1021/acs.biochem.9b00741. PMID:31917549 doi:http://dx.doi.org/10.1021/acs.biochem.9b00741
