Structural #studies of #Chikungunya virus #maturation (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Structural studies of Chikungunya virus maturation

Moh Lan Yap a,b, Thomas Klose a, Akane Urakami c, S. Saif Hasan a, Wataru Akahata c, and Michael G. Rossmann a,1

Author Affiliations: a Department of Biological Sciences, Purdue University, West Lafayette, IN 47907;  b Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, 31900 Kampar, Perak, Malaysia; c VLP Therapeutics, Gaithersburg, MD 20878

Edited by Robert M. Stroud, University of California, San Francisco, California, and approved November 10, 2017 (received for review July 25, 2017)

 

Significance

Chikungunya virus (CHIKV) belongs to the alphavirus family, the members of which have enveloped icosahedral capsids. The maturation process of alphaviruses involves proteolysis of some of the structural proteins before assembling with nucleocapsids to produce mature virions. We mutated the proteolytic cleavage site on E2 envelope protein, which is necessary in initiating the maturation process. Noninfectious virus-like particles (VLP) equivalent to “immature” fusion incompetent particles were produced to study the immature conformation of CHIKV. We describe the 6.8-Å resolution electron microscopy structure of “immature” CHIK VLPs. Structural differences between the mature and immature VLPs show that posttranslational processing of the envelope proteins and nucleocapsid is necessary to allow exposure of the fusion loop on glycoprotein E1 to produce an infectious virus.

 

Abstract

Cleavage of the alphavirus precursor glycoprotein p62 into the E2 and E3 glycoproteins before assembly with the nucleocapsid is the key to producing fusion-competent mature spikes on alphaviruses. Here we present a cryo-EM, 6.8-Å resolution structure of an “immature” Chikungunya virus in which the cleavage site has been mutated to inhibit proteolysis. The spikes in the immature virus have a larger radius and are less compact than in the mature virus. Furthermore, domains B on the E2 glycoproteins have less freedom of movement in the immature virus, keeping the fusion loops protected under domain B. In addition, the nucleocapsid of the immature virus is more compact than in the mature virus, protecting a conserved ribosome-binding site in the capsid protein from exposure. These differences suggest that the posttranslational processing of the spikes and nucleocapsid is necessary to produce infectious virus.

alphavirus – Chikungunya virus – maturation – cryo-electron microscopy – conformational changes

 

Footnotes

1 To whom correspondence should be addressed. Email: mr@purdue.edu.

Author contributions: M.L.Y. and M.G.R. designed research; M.L.Y., T.K., A.U., and W.A. performed research; M.L.Y. and S.S.H. analyzed data; and M.L.Y. and M.G.R. wrote the paper.

Conflict of interest statement: M.L.Y., T.K., S.S.H., and M.G.R. declare no competing financial interests. A.U. is an employee of VLP Therapeutics, and W.A. is an officer and shareholder of VLP Therapeutics.

This article is a PNAS Direct Submission.

Data deposition: The final immature Chikungunya VLP electron density map was deposited in the Electron Microscopy Data Bank, https://www.emdatabank.org (accession code EMD-8734), and structure coordinates have been deposited in the Protein Data Bank, http://www.rcsb.org/pdb (PDB ID code 5VU2).

This article contains supporting information online at http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1713166114/-/DCSupplemental.

Published under the PNAS license.

Keywords: Alphavirus; Chikungunya Fever.

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gimi69

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.

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