Molecular Determinants Defining the Triggering Range of Prefusion F Complexes of Canine Distemper Virus

Avila, Mislay; Alves, Lisa; Khosravi, Mojtaba; Ader-Ebert, Nadine; Origgi, Francesco; Schneider-Schaulies, J.; Zurbriggen, Andreas; Plemper, R. K.; Plattet, Philippe; Lyles, D. S. (2014). Molecular Determinants Defining the Triggering Range of Prefusion F Complexes of Canine Distemper Virus. Journal of virology, 88(5), pp. 2951-2966. American Society for Microbiology 10.1128/JVI.03123-13

[img] Text
J. Virol.-2014-Avila-2951-66.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (6MB) | Request a copy

The morbillivirus cell entry machinery consists of a fusion (F) protein trimer that refolds to mediate membrane fusion following receptor-induced conformational changes in its binding partner, the tetrameric attachment (H) protein. To identify molecular determinants that control F refolding, we generated F chimeras between measles virus (MeV) and canine distemper virus (CDV). We located a central pocket in the globular head domain of CDV F that regulates the stability of the metastable, prefusion conformational state of the F trimer. Most mutations introduced into this "pocket'" appeared to mediate a destabilizing effect, a phenotype associated with enhanced membrane fusion activity. Strikingly, under specific triggering conditions (i.e., variation of receptor type and H protein origin), some F mutants also exhibited resistance to a potent morbillivirus entry inhibitor, which is known to block F triggering by enhancing the stability of prefusion F trimers. Our data reveal that the molecular nature of the F stimulus and the intrinsic stability of metastable prefusion F both regulate the efficiency of F refolding and escape from small-molecule refolding blockers. IMPORTANCE: With the aim to better characterize the thermodynamic basis of morbillivirus membrane fusion for cell entry and spread, we report here that the activation energy barrier of prefusion F trimers together with the molecular nature of the triggering "stimulus" (attachment protein and receptor types) define a "triggering range," which governs the initiation of the membrane fusion process. A central "pocket" microdomain in the globular F head contributes substantially to the regulation of the conformational stability of the prefusion complexes. The triggering range also defines the mechanism of viral escape from entry inhibitors and describes how the cellular environment can affect membrane fusion efficiency.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > NeuroCenter
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > DKV - Clinical Neurology
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV)
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)
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Veterinary Bacteriology

UniBE Contributor:

Avila, Mislay; Cardoso Alves, Lisa Alexandra; Khosravi, Mojtaba; Ebert, Nadine; Origgi, Francesco; Zurbriggen, Andreas and Plattet, Philippe

Subjects:

600 Technology > 630 Agriculture

ISSN:

0022-538X

Publisher:

American Society for Microbiology

Language:

English

Submitter:

Susanne Portner

Date Deposited:

22 Aug 2014 15:04

Last Modified:

14 Oct 2015 11:12

Publisher DOI:

10.1128/JVI.03123-13

PubMed ID:

24371057

BORIS DOI:

10.7892/boris.41923

URI:

https://boris.unibe.ch/id/eprint/41923

Actions (login required)

Edit item Edit item
Provide Feedback