Structure of a Phleboviral Envelope Glycoprotein Reveals a Consolidated Model of Membrane Fusion

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2016 Jun 22

PMID 27325770

Citations 65

Authors

Steinar Halldorsson

Anna-Janina Behrens

Karl Harlos

Juha T Huiskonen

Richard M Elliott

Max Crispin

Benjamin Brennan

Thomas A Bowden

Affiliations

Soon will be listed here.

Abstract

An emergent viral pathogen termed severe fever with thrombocytopenia syndrome virus (SFTSV) is responsible for thousands of clinical cases and associated fatalities in China, Japan, and South Korea. Akin to other phleboviruses, SFTSV relies on a viral glycoprotein, Gc, to catalyze the merger of endosomal host and viral membranes during cell entry. Here, we describe the postfusion structure of SFTSV Gc, revealing that the molecular transformations the phleboviral Gc undergoes upon host cell entry are conserved with otherwise unrelated alpha- and flaviviruses. By comparison of SFTSV Gc with that of the prefusion structure of the related Rift Valley fever virus, we show that these changes involve refolding of the protein into a trimeric state. Reverse genetics and rescue of site-directed histidine mutants enabled localization of histidines likely to be important for triggering this pH-dependent process. These data provide structural and functional evidence that the mechanism of phlebovirus-host cell fusion is conserved among genetically and patho-physiologically distinct viral pathogens.

Citing Articles

The Role of Orthobunyavirus Glycoprotein Gc in the Viral Life Cycle: From Viral Entry to Egress.

Gao H, Zhao D, Li C, Deng M, Li G, Chen S Molecules. 2025; 30(3).

PMID: 39942606 PMC: 11820035. DOI: 10.3390/molecules30030503.

Safety, Immunogenicity, and Efficacy of a Recombinant Vesicular Stomatitis Virus Vectored Vaccine Against Severe Fever with Thrombocytopenia Syndrome Virus and Heartland Bandavirus.

Hicks P, Manzoni T, Westover J, Petch R, Roper B, Gowen B Vaccines (Basel). 2025; 12(12.

PMID: 39772063 PMC: 11728676. DOI: 10.3390/vaccines12121403.

Discovery and characterization of potent broadly neutralizing antibodies from human survivors of severe fever with thrombocytopenia syndrome.

Zhang S, Shang H, Han S, Li J, Peng X, Wu Y EBioMedicine. 2024; 111():105481.

PMID: 39644769 PMC: 11665701. DOI: 10.1016/j.ebiom.2024.105481.

N6-methyladenosine RNA modification promotes Severe Fever with Thrombocytopenia Syndrome Virus infection.

Chen Z, Zhang J, Wang J, Tong H, Pan W, Ma F PLoS Pathog. 2024; 20(11):e1012725.

PMID: 39585899 PMC: 11627400. DOI: 10.1371/journal.ppat.1012725.

Adenovirus type 5-expressing Gn induces better protective immunity than Gc against SFTSV infection in mice.

Qian H, Tian L, Liu W, Liu L, Li M, Zhao Z NPJ Vaccines. 2024; 9(1):194.

PMID: 39426985 PMC: 11490641. DOI: 10.1038/s41541-024-00993-y.

References

Sievers F, Wilm A, Dineen D, Gibson T, Karplus K, Li W . Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011; 7:539. PMC: 3261699. DOI: 10.1038/msb.2011.75. View

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

de Boer S, Kortekaas J, Spel L, Rottier P, Moormann R, Bosch B . Acid-activated structural reorganization of the Rift Valley fever virus Gc fusion protein. J Virol. 2012; 86(24):13642-52. PMC: 3503025. DOI: 10.1128/JVI.01973-12. View

Kampmann T, Mueller D, Mark A, Young P, Kobe B . The Role of histidine residues in low-pH-mediated viral membrane fusion. Structure. 2006; 14(10):1481-7. DOI: 10.1016/j.str.2006.07.011. View

Roussel A, Lescar J, Vaney M, Wengler G, Wengler G, Rey F . Structure and interactions at the viral surface of the envelope protein E1 of Semliki Forest virus. Structure. 2006; 14(1):75-86. DOI: 10.1016/j.str.2005.09.014. View

Chen V, Arendall 3rd W, Headd J, Keedy D, Immormino R, Kapral G . MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):12-21. PMC: 2803126. DOI: 10.1107/S0907444909042073. View

Cui N, Liu R, Lu Q, Wang L, Qin S, Yang Z . Severe fever with thrombocytopenia syndrome bunyavirus-related human encephalitis. J Infect. 2014; 70(1):52-9. DOI: 10.1016/j.jinf.2014.08.001. View

Qin Z, Zheng Y, Kielian M . Role of conserved histidine residues in the low-pH dependence of the Semliki Forest virus fusion protein. J Virol. 2009; 83(9):4670-7. PMC: 2668505. DOI: 10.1128/JVI.02646-08. View

Stiasny K, Allison S, Kunz C, Heinz F . Structural requirements for low-pH-induced rearrangements in the envelope glycoprotein of tick-borne encephalitis virus. J Virol. 1996; 70(11):8142-7. PMC: 190891. DOI: 10.1128/JVI.70.11.8142-8147.1996. View

10.

Ding F, Zhang W, Wang L, Hu W, Soares Magalhaes R, Sun H . Epidemiologic features of severe fever with thrombocytopenia syndrome in China, 2011-2012. Clin Infect Dis. 2013; 56(11):1682-3. DOI: 10.1093/cid/cit100. View

11.

Dessau M, Modis Y . Crystal structure of glycoprotein C from Rift Valley fever virus. Proc Natl Acad Sci U S A. 2013; 110(5):1696-701. PMC: 3562824. DOI: 10.1073/pnas.1217780110. View

12.

Cowtan K . The Buccaneer software for automated model building. 1. Tracing protein chains. Acta Crystallogr D Biol Crystallogr. 2006; 62(Pt 9):1002-11. DOI: 10.1107/S0907444906022116. View

13.

Klimstra W, Nangle E, Smith M, Yurochko A, Ryman K . DC-SIGN and L-SIGN can act as attachment receptors for alphaviruses and distinguish between mosquito cell- and mammalian cell-derived viruses. J Virol. 2003; 77(22):12022-32. PMC: 254289. DOI: 10.1128/jvi.77.22.12022-12032.2003. View

14.

Neville D, Dwek R, Butters T . Development of a single column method for the separation of lipid- and protein-derived oligosaccharides. J Proteome Res. 2008; 8(2):681-7. DOI: 10.1021/pr800704t. View

15.

Modis Y, Ogata S, Clements D, Harrison S . Structure of the dengue virus envelope protein after membrane fusion. Nature. 2004; 427(6972):313-9. DOI: 10.1038/nature02165. View

16.

Lescar J, Roussel A, Wien M, Navaza J, Fuller S, WENGLER G . The Fusion glycoprotein shell of Semliki Forest virus: an icosahedral assembly primed for fusogenic activation at endosomal pH. Cell. 2001; 105(1):137-48. DOI: 10.1016/s0092-8674(01)00303-8. View

17.

Heckman K, Pease L . Gene splicing and mutagenesis by PCR-driven overlap extension. Nat Protoc. 2007; 2(4):924-32. DOI: 10.1038/nprot.2007.132. View

18.

Rey F, Heinz F, Mandl C, Kunz C, Harrison S . The envelope glycoprotein from tick-borne encephalitis virus at 2 A resolution. Nature. 1995; 375(6529):291-8. DOI: 10.1038/375291a0. View

19.

Crispin M, Harvey D, Bitto D, Halldorsson S, Bonomelli C, Edgeworth M . Uukuniemi Phlebovirus assembly and secretion leave a functional imprint on the virion glycome. J Virol. 2014; 88(17):10244-51. PMC: 4136308. DOI: 10.1128/JVI.01662-14. View

20.

Vaney M, Rey F . Class II enveloped viruses. Cell Microbiol. 2011; 13(10):1451-9. DOI: 10.1111/j.1462-5822.2011.01653.x. View