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Structural Transition of GP64 Triggered by a PH-sensitive Multi-histidine Switch

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Journal Nat Commun
Specialty Biology
Date 2024 Sep 3
PMID 39227374
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Abstract

The fusion of viruses with cellular membranes is a critical step in the life cycle of enveloped viruses. This process is facilitated by viral fusion proteins, many of which are conformationally pH-sensitive. The specifics of how changes in pH initiate this fusion have remained largely elusive. This study presents the cryo-electron microscopy (cryo-EM) structures of a prototype class III fusion protein, GP64, in its prefusion and early intermediate states, revealing the structural intermediates accompanying the membrane fusion process. The structures identify the involvement of a pH-sensitive switch, comprising H23, H245, and H304, in sensing the low pH that triggers the initial step of membrane fusion. The pH sensing role of this switch is corroborated by assays of cell-cell syncytium formation and dual dye-labeling. The findings demonstrate that coordination between multiple histidine residues acts as a pH sensor and activator. The involvement of a multi-histidine switch in viral fusion is applicable to fusogens of human-infecting thogotoviruses and other viruses, which could lead to strategies for developing anti-viral therapies and vaccines.

Citing Articles

Unraveling dual fusion mechanisms in BmNPV GP64: critical roles of CARC motifs and signal peptide retention.

Sun L, Xu Y, Chen K, Nan W, Wang M, Zhang Y J Virol. 2024; 99(1):e0151124.

PMID: 39601591 PMC: 11784077. DOI: 10.1128/jvi.01511-24.

References
1.
Matsuura H, Kirschner A, Longnecker R, Jardetzky T . Crystal structure of the Epstein-Barr virus (EBV) glycoprotein H/glycoprotein L (gH/gL) complex. Proc Natl Acad Sci U S A. 2010; 107(52):22641-6. PMC: 3012493. DOI: 10.1073/pnas.1011806108. View

2.
Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

3.
Li Z, Blissard G . Autographa californica multiple nucleopolyhedrovirus GP64 protein: roles of histidine residues in triggering membrane fusion and fusion pore expansion. J Virol. 2011; 85(23):12492-504. PMC: 3209339. DOI: 10.1128/JVI.05153-11. View

4.
Li Z, Blissard G . The Autographa californica multicapsid nucleopolyhedrovirus GP64 protein: analysis of transmembrane domain length and sequence requirements. J Virol. 2009; 83(9):4447-61. PMC: 2668483. DOI: 10.1128/JVI.02252-08. View

5.
Podbilewicz B . Virus and cell fusion mechanisms. Annu Rev Cell Dev Biol. 2014; 30:111-39. DOI: 10.1146/annurev-cellbio-101512-122422. View