GP1 of Lassa Virus

From Proteopedia

Glycosylated receptor binding domain of Lassa Virus (PDB code 4zjf) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Contents 1 Importance 2 Function 3 Structural Highlights 3.1 LAMP1 Binding Site 3.2 Histidine Triad 4 Resources Importance Lassa virus (LASV), an Old World (OW) arenavirus, is a notorious disease-causing agent primarily in West Africa that is able to spread from rodents to humans. This deadly pathogen causes severe viral hemorrhagic fevers and significant mortality. So far, there are no available vaccines for LASV, and only one successful vaccine against another virus found in the Arenaviridae family: Junin virus[1]. Structural data at atomic resolution for viral proteins are laying the foundation for better understanding both the biology behind viral proteins and ways to combat against them. Determining the structure of the complete trimeric glycoprotein complex (GPC), composed of GP1, GP2, and SSP (stable signal peptide), will pave the path towards a future discovery of novel antiviral drugs. This is the first representative structure for OW arenaviruses. This structure reveals the overall architecture of GP1 domains from OW arenaviruses and important information relating to the mechanisms for pH switching and the binding of LASV to LAMP1 (Lysosome-associated membrane glycoprotein), a recently identified host receptor that is critical for successful infection. In addition, structural analysis suggests two novel immune evasion mechanisms that LASV may utilize to escape antibody-based immune response. Function GP1 (Glycoprotein 1) is the receptor binding domain of LASV that mediates receptor recognition. Research thus far indicates that GP1 from LASV may undergo irreversible conformational changes that could serve as an immunological decoy mechanism. Arenaviruses utilize various cell surface proteins as their cellular receptors for recognizing and attaching to target cells. New World (NW) arenaviruses that belong to clades A and B use transferrin receptor 1 (TfR1)[2][3], whereas OW arenaviruses, as well as clade C NW arenaviruses, use α-dystroglycan (α-DG) [4][5][6]. A trimeric class 1 viral glycoprotein complex (the spike complex) recognizes the cellular receptors and mediates membrane fusion upon exposure to low pH at the lysosome [7]. The spike complex is expressed as a glycoprotein precursor that is cleaved into three segments by a signal peptidase and SKI-1/S1P protease[8]. The functional spike complex consists of GP1, a membrane-anchored fusion protein (GP2), and a unique structured SSP [9]. Structural Highlights GP1 of LASV is a single chain structure with attached glycans. The overall architecture of GP1 features a central β-sheet and two distinct halves: a glycosylated half containing the receptor-binding site that is made mostly by the central β-sheet and surrounding loops and a half that contains mostly helices and most likely faces the trimer axis[10], as determined in the Diskin laboratory at the Weizmann Institute of Science. The method used to determine this structure was X-ray diffraction LAMP1 Binding Site The primary cellular receptor of LASV is α-dystroglycan (α-DG)[11][12], which is recognized by a trimeric class 1 viral GPC (spike complex) on the viral surface[13][14]. Following successful attachment to α-DG on cells, LASV is internalized via macropinocytosis[15], and the GPC facilitates membrane fusion at the acidic environment of a late endosomal compartment[13]. Recent studies have shown that successful infection by LASV requires it to switch in a pH-dependent manner from α-DG to LAMP1[16][17]. Binding of the endosomal compartment triggers the spikes. Histidine Triad Included in this structure is a unique that is highly conserved among OW arenaviruses. Located on the β-sheet face of GP1, the histidine triad is a structural element that directly interacts with LAMP1 and helps stabilize a LAMP1-"compatible" conformation by providing a molecular mechanism for the pH-dependent receptor switching[10]. The is critical in forming a for LAMP1[16][18]. Resources For more information on this protein structure visit the following sites: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

References

1. ↑ Maiztegui JI, McKee KT Jr, Barrera Oro JG, Harrison LH, Gibbs PH, Feuillade MR, Enria DA, Briggiler AM, Levis SC, Ambrosio AM, Halsey NA, Peters CJ. Protective efficacy of a live attenuated vaccine against Argentine hemorrhagic fever. AHF Study Group. J Infect Dis. 1998 Feb;177(2):277-83. PMID:9466512
2. ↑ Radoshitzky SR, Abraham J, Spiropoulou CF, Kuhn JH, Nguyen D, Li W, Nagel J, Schmidt PJ, Nunberg JH, Andrews NC, Farzan M, Choe H. Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses. Nature. 2007 Mar 1;446(7131):92-6. Epub 2007 Feb 7. PMID:17287727 doi:http://dx.doi.org/10.1038/nature05539
3. ↑ Zong M, Fofana I, Choe H. Human and host species transferrin receptor 1 use by North American arenaviruses. J Virol. 2014 Aug;88(16):9418-28. doi: 10.1128/JVI.01112-14. Epub 2014 Jun 11. PMID:24920811 doi:http://dx.doi.org/10.1128/JVI.01112-14
4. ↑ Cao W, Henry MD, Borrow P, Yamada H, Elder JH, Ravkov EV, Nichol ST, Compans RW, Campbell KP, Oldstone MB. Identification of alpha-dystroglycan as a receptor for lymphocytic choriomeningitis virus and Lassa fever virus. Science. 1998 Dec 11;282(5396):2079-81. PMID:9851928
5. ↑ Kunz S, Rojek JM, Perez M, Spiropoulou CF, Oldstone MB. Characterization of the interaction of lassa fever virus with its cellular receptor alpha-dystroglycan. J Virol. 2005 May;79(10):5979-87. PMID:15857984 doi:http://dx.doi.org/10.1128/JVI.79.10.5979-5987.2005
6. ↑ Spiropoulou CF, Kunz S, Rollin PE, Campbell KP, Oldstone MB. New World arenavirus clade C, but not clade A and B viruses, utilizes alpha-dystroglycan as its major receptor. J Virol. 2002 May;76(10):5140-6. PMID:11967329
7. ↑ Eschli B, Quirin K, Wepf A, Weber J, Zinkernagel R, Hengartner H. Identification of an N-terminal trimeric coiled-coil core within arenavirus glycoprotein 2 permits assignment to class I viral fusion proteins. J Virol. 2006 Jun;80(12):5897-907. PMID:16731928 doi:http://dx.doi.org/10.1128/JVI.00008-06
8. ↑ Pasquato A, Burri DJ, Traba EG, Hanna-El-Daher L, Seidah NG, Kunz S. Arenavirus envelope glycoproteins mimic autoprocessing sites of the cellular proprotein convertase subtilisin kexin isozyme-1/site-1 protease. Virology. 2011 Aug 15;417(1):18-26. doi: 10.1016/j.virol.2011.04.021. Epub 2011, May 25. PMID:21612810 doi:http://dx.doi.org/10.1016/j.virol.2011.04.021
9. ↑ Burri DJ, da Palma JR, Kunz S, Pasquato A. Envelope glycoprotein of arenaviruses. Viruses. 2012 Oct 17;4(10):2162-81. doi: 10.3390/v4102162. PMID:23202458 doi:http://dx.doi.org/10.3390/v4102162
10. ↑ ^{10.0 10.1} Cohen-Dvashi H, Cohen N, Israeli H, Diskin R. Molecular mechanism for LAMP1 recognition by Lassa Virus. J Virol. 2015 May 13. pii: JVI.00651-15. PMID:25972533 doi:http://dx.doi.org/10.1128/JVI.00651-15
11. ↑ Cao W, Henry MD, Borrow P, Yamada H, Elder JH, Ravkov EV, Nichol ST, Compans RW, Campbell KP, Oldstone MB. Identification of alpha-dystroglycan as a receptor for lymphocytic choriomeningitis virus and Lassa fever virus. Science. 1998 Dec 11;282(5396):2079-81. PMID:9851928
12. ↑ Kunz S, Rojek JM, Perez M, Spiropoulou CF, Oldstone MB. Characterization of the interaction of lassa fever virus with its cellular receptor alpha-dystroglycan. J Virol. 2005 May;79(10):5979-87. PMID:15857984 doi:http://dx.doi.org/10.1128/JVI.79.10.5979-5987.2005
13. ↑ ^{13.0 13.1} Eschli B, Quirin K, Wepf A, Weber J, Zinkernagel R, Hengartner H. Identification of an N-terminal trimeric coiled-coil core within arenavirus glycoprotein 2 permits assignment to class I viral fusion proteins. J Virol. 2006 Jun;80(12):5897-907. PMID:16731928 doi:http://dx.doi.org/10.1128/JVI.00008-06
14. ↑ Li S, Sun Z, Pryce R, Parsy ML, Fehling SK, Schlie K, Siebert CA, Garten W, Bowden TA, Strecker T, Huiskonen JT. Acidic pH-Induced Conformations and LAMP1 Binding of the Lassa Virus Glycoprotein Spike. PLoS Pathog. 2016 Feb 5;12(2):e1005418. doi: 10.1371/journal.ppat.1005418., eCollection 2016 Feb. PMID:26849049 doi:http://dx.doi.org/10.1371/journal.ppat.1005418
15. ↑ Oppliger J, Torriani G, Herrador A, Kunz S. Lassa Virus Cell Entry via Dystroglycan Involves an Unusual Pathway of Macropinocytosis. J Virol. 2016 Jun 24;90(14):6412-29. doi: 10.1128/JVI.00257-16. Print 2016 Jul, 15. PMID:27147735 doi:http://dx.doi.org/10.1128/JVI.00257-16
16. ↑ ^{16.0 16.1} Cohen-Dvashi H, Israeli H, Shani O, Katz A, Diskin R. Role of LAMP1 Binding and pH Sensing by the Spike Complex of Lassa Virus. J Virol. 2016 Oct 28;90(22):10329-10338. Print 2016 Nov 15. PMID:27605678 doi:http://dx.doi.org/10.1128/JVI.01624-16
17. ↑ Jae LT, Raaben M, Herbert AS, Kuehne AI, Wirchnianski AS, Soh TK, Stubbs SH, Janssen H, Damme M, Saftig P, Whelan SP, Dye JM, Brummelkamp TR. Virus entry. Lassa virus entry requires a trigger-induced receptor switch. Science. 2014 Jun 27;344(6191):1506-10. doi: 10.1126/science.1252480. PMID:24970085 doi:http://dx.doi.org/10.1126/science.1252480
18. ↑ Israeli H, Cohen-Dvashi H, Shulman A, Shimon A, Diskin R. Mapping of the Lassa virus LAMP1 binding site reveals unique determinants not shared by other old world arenaviruses. PLoS Pathog. 2017 Apr 27;13(4):e1006337. doi: 10.1371/journal.ppat.1006337., eCollection 2017 Apr. PMID:28448640 doi:http://dx.doi.org/10.1371/journal.ppat.1006337