Organisation of the orthobunyavirus tripodal spike and the structural changes induced by low pH and K+ during entry

Abstract

Following endocytosis, enveloped viruses employ the changing environment of maturing endosomes as cues to promote endosomal escape, a process often mediated by viral glycoproteins. We previously showed that both high [K+] and low pH promote entry of Bunyamwera virus (BUNV), the prototypical bunyavirus. Here, we use sub-tomogram averaging and AlphaFold, to generate a pseudo-atomic model of the whole BUNV glycoprotein envelope. We unambiguously locate the Gc fusion domain and its chaperone Gn within the floor domain of the spike. Furthermore, viral incubation at low pH and high [K+], reminiscent of endocytic conditions, results in a dramatic rearrangement of the BUNV envelope. Structural and biochemical assays indicate that pH 6.3/K+ in the absence of a target membrane elicits a fusion-capable triggered intermediate state of BUNV GPs; but the same conditions induce fusion when target membranes are present. Taken together, we provide mechanistic understanding of the requirements for bunyavirus entry.

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Item Type:	Article
Authors/Creators:	Hover, S. Charlton, F.W. Hellert, J. Swanson, J.J. Mankouri, J. Barr, J.N. Fontana, J. https://orcid.org/0000-0002-9084-2927
Copyright, Publisher and Additional Information:	© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/.
Dates:	Published: 21 September 2023 Published (online): 21 September 2023 Accepted: 5 September 2023
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds)
Funding Information:	Funder Grant number Human Frontier Science Program RGP0040/2019 Academy of Medical Sciences SBF002\1029 Rosetrees Trust A1618 MRC (Medical Research Council) MR/T016159/1 Wellcome Trust 108466/Z/15/Z Wellcome Trust 090932/Z/09/Z BBSRC (Biotechnology & Biological Sciences Research Council) BB/P001459/1
Depositing User:	Symplectic Publications
Date Deposited:	08 Sep 2023 11:27
Last Modified:	22 Sep 2023 12:45
Published Version:	https://www.nature.com/articles/s41467-023-41205-w
Status:	Published
Publisher:	Nature Research
Identification Number:	10.1038/s41467-023-41205-w
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:203167

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Organisation of the orthobunyavirus tripodal spike and the structural changes induced by low pH and K+ during entry

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