Crystal Structure of the Conserved Herpesvirus Fusion Regulator Complex GH-gL

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2010 Jul 6

PMID 20601960

Citations 173

Authors

Tirumala K Chowdary

Tina M Cairns

Doina Atanasiu

Gary H Cohen

Roselyn J Eisenberg

Ekaterina E Heldwein

Affiliations

Soon will be listed here.

Abstract

Herpesviruses, which cause many incurable diseases, infect cells by fusing viral and cellular membranes. Whereas most other enveloped viruses use a single viral catalyst called a fusogen, herpesviruses, inexplicably, require two conserved fusion-machinery components, gB and the heterodimer gH-gL, plus other nonconserved components. gB is a class III viral fusogen, but unlike other members of its class, it does not function alone. We determined the crystal structure of the gH ectodomain bound to gL from herpes simplex virus 2. gH-gL is an unusually tight complex with a unique architecture that, unexpectedly, does not resemble any known viral fusogen. Instead, we propose that gH-gL activates gB for fusion, possibly through direct binding. Formation of a gB-gH-gL complex is critical for fusion and is inhibited by a neutralizing antibody, making the gB-gH-gL interface a promising antiviral target.

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References

Buckmaster E, Gompels U, Minson A . Characterisation and physical mapping of an HSV-1 glycoprotein of approximately 115 X 10(3) molecular weight. Virology. 1984; 139(2):408-13. DOI: 10.1016/0042-6822(84)90387-8. View

Atanasiu D, Whitbeck J, Cairns T, Reilly B, Cohen G, Eisenberg R . Bimolecular complementation reveals that glycoproteins gB and gH/gL of herpes simplex virus interact with each other during cell fusion. Proc Natl Acad Sci U S A. 2007; 104(47):18718-23. PMC: 2141843. DOI: 10.1073/pnas.0707452104. View

Hutchinson L, Browne H, Wargent V, Davis-Poynter N, Primorac S, Goldsmith K . A novel herpes simplex virus glycoprotein, gL, forms a complex with glycoprotein H (gH) and affects normal folding and surface expression of gH. J Virol. 1992; 66(4):2240-50. PMC: 289017. DOI: 10.1128/JVI.66.4.2240-2250.1992. View

Otwinowski Z, Minor W . Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 1997; 276:307-26. DOI: 10.1016/S0076-6879(97)76066-X. View

Farnsworth A, Wisner T, Webb M, Roller R, Cohen G, Eisenberg R . Herpes simplex virus glycoproteins gB and gH function in fusion between the virion envelope and the outer nuclear membrane. Proc Natl Acad Sci U S A. 2007; 104(24):10187-92. PMC: 1891206. DOI: 10.1073/pnas.0703790104. View

Spear P, Longnecker R . Herpesvirus entry: an update. J Virol. 2003; 77(19):10179-85. PMC: 228481. DOI: 10.1128/jvi.77.19.10179-10185.2003. View

Roche S, Bressanelli S, Rey F, Gaudin Y . Crystal structure of the low-pH form of the vesicular stomatitis virus glycoprotein G. Science. 2006; 313(5784):187-91. DOI: 10.1126/science.1127683. View

PATERSON R, Hiebert S, Lamb R . Expression at the cell surface of biologically active fusion and hemagglutinin/neuraminidase proteins of the paramyxovirus simian virus 5 from cloned cDNA. Proc Natl Acad Sci U S A. 1985; 82(22):7520-4. PMC: 390848. DOI: 10.1073/pnas.82.22.7520. View

Corpet F . Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res. 1988; 16(22):10881-90. PMC: 338945. DOI: 10.1093/nar/16.22.10881. View

10.

Krissinel E, Henrick K . Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 12 Pt 1):2256-68. DOI: 10.1107/S0907444904026460. View

11.

Backovic M, Jardetzky T . Class III viral membrane fusion proteins. Curr Opin Struct Biol. 2009; 19(2):189-96. PMC: 3076093. DOI: 10.1016/j.sbi.2009.02.012. View

12.

LARKIN M, Blackshields G, Brown N, Chenna R, McGettigan P, McWilliam H . Clustal W and Clustal X version 2.0. Bioinformatics. 2007; 23(21):2947-8. DOI: 10.1093/bioinformatics/btm404. View

13.

Barton G . ALSCRIPT: a tool to format multiple sequence alignments. Protein Eng. 1993; 6(1):37-40. DOI: 10.1093/protein/6.1.37. View

14.

Galdiero S, Falanga A, Vitiello M, Browne H, Pedone C, Galdiero M . Fusogenic domains in herpes simplex virus type 1 glycoprotein H. J Biol Chem. 2005; 280(31):28632-43. DOI: 10.1074/jbc.M505196200. View

15.

Cairns T, Friedman L, Lou H, Whitbeck J, Shaner M, Cohen G . N-terminal mutants of herpes simplex virus type 2 gH are transported without gL but require gL for function. J Virol. 2007; 81(10):5102-11. PMC: 1900195. DOI: 10.1128/JVI.00097-07. View

16.

Ryckman B, Rainish B, Chase M, Borton J, Nelson J, Jarvis M . Characterization of the human cytomegalovirus gH/gL/UL128-131 complex that mediates entry into epithelial and endothelial cells. J Virol. 2007; 82(1):60-70. PMC: 2224386. DOI: 10.1128/JVI.01910-07. View

17.

Davis I, Leaver-Fay A, Chen V, Block J, Kapral G, Wang X . MolProbity: all-atom contacts and structure validation for proteins and nucleic acids. Nucleic Acids Res. 2007; 35(Web Server issue):W375-83. PMC: 1933162. DOI: 10.1093/nar/gkm216. View

18.

Showalter S, ZWEIG M, Hampar B . Monoclonal antibodies to herpes simplex virus type 1 proteins, including the immediate-early protein ICP 4. Infect Immun. 1981; 34(3):684-92. PMC: 350925. DOI: 10.1128/iai.34.3.684-692.1981. View

19.

Avitabile E, Forghieri C, Campadelli-Fiume G . Complexes between herpes simplex virus glycoproteins gD, gB, and gH detected in cells by complementation of split enhanced green fluorescent protein. J Virol. 2007; 81(20):11532-7. PMC: 2045520. DOI: 10.1128/JVI.01343-07. View

20.

Gouet P, Courcelle E, Stuart D, Metoz F . ESPript: analysis of multiple sequence alignments in PostScript. Bioinformatics. 1999; 15(4):305-8. DOI: 10.1093/bioinformatics/15.4.305. View