Sequential conformational changes in the morbillivirus attachment protein initiate the membrane fusion process.

Ader-Ebert, Nadine; Khosravi, Mojtaba; Herren, Michael; Avila Sanchez, Mislay; Alves, Lisa; Bringolf, Fanny Anne; Örvell, Claes; Langedijk, Johannes P; Zurbriggen, Andreas; Plemper, Richard K; Plattet, Philippe (2015). Sequential conformational changes in the morbillivirus attachment protein initiate the membrane fusion process. PLoS pathogens, 11(5), e1004880. Public Library of Science 10.1371/journal.ppat.1004880

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Despite large vaccination campaigns, measles virus (MeV) and canine distemper virus (CDV) cause major morbidity and mortality in humans and animals, respectively. The MeV and CDV cell entry system relies on two interacting envelope glycoproteins: the attachment protein (H), consisting of stalk and head domains, co-operates with the fusion protein (F) to mediate membrane fusion. However, how receptor-binding by the H-protein leads to F-triggering is not fully understood. Here, we report that an anti-CDV-H monoclonal antibody (mAb-1347), which targets the linear H-stalk segment 126-133, potently inhibits membrane fusion without interfering with H receptor-binding or F-interaction. Rather, mAb-1347 blocked the F-triggering function of H-proteins regardless of the presence or absence of the head domains. Remarkably, mAb-1347 binding to headless CDV H, as well as standard and engineered bioactive stalk-elongated CDV H-constructs treated with cells expressing the SLAM receptor, was enhanced. Despite proper cell surface expression, fusion promotion by most H-stalk mutants harboring alanine substitutions in the 126-138 "spacer" section was substantially impaired, consistent with deficient receptor-induced mAb-1347 binding enhancement. However, a previously reported F-triggering defective H-I98A variant still exhibited the receptor-induced "head-stalk" rearrangement. Collectively, our data spotlight a distinct mechanism for morbillivirus membrane fusion activation: prior to receptor contact, at least one of the morbillivirus H-head domains interacts with the membrane-distal "spacer" domain in the H-stalk, leaving the F-binding site located further membrane-proximal in the stalk fully accessible. This "head-to-spacer" interaction conformationally stabilizes H in an auto-repressed state, which enables intracellular H-stalk/F engagement while preventing the inherent H-stalk's bioactivity that may prematurely activate F. Receptor-contact disrupts the "head-to-spacer" interaction, which subsequently "unlocks" the stalk, allowing it to rearrange and trigger F. Overall, our study reveals essential mechanistic requirements governing the activation of the morbillivirus membrane fusion cascade and spotlights the H-stalk "spacer" microdomain as a possible drug target for antiviral therapy.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > NeuroCenter
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Experimental Clinical Research
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Ebert, Nadine; Khosravi, Mojtaba; Herren, Michael; Avila Sanchez, Mislay; Bringolf, Fanny Anne; Zurbriggen, Andreas and Plattet, Philippe

Subjects:

600 Technology > 630 Agriculture

ISSN:

1553-7366

Publisher:

Public Library of Science

Language:

English

Submitter:

Susanne Portner

Date Deposited:

14 Oct 2016 18:04

Last Modified:

04 Sep 2018 08:36

Publisher DOI:

10.1371/journal.ppat.1004880

PubMed ID:

25946112

BORIS DOI:

10.7892/boris.89320

URI:

https://boris.unibe.ch/id/eprint/89320

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