Structures and Functions of the Envelope Glycoprotein in Flavivirus Infections

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Abstract

Flaviviruses are enveloped, single-stranded RNA viruses that widely infect many animal species. The envelope protein, a structural protein of flavivirus, plays an important role in host cell viral infections. It is composed of three separate structural envelope domains I, II, and III (EDI, EDII, and EDIII). EDI is a structurally central domain of the envelope protein which stabilizes the overall orientation of the protein, and the glycosylation sites in EDI are related to virus production, pH sensitivity, and neuroinvasiveness. EDII plays an important role in membrane fusion because of the immunodominance of the fusion loop epitope and the envelope dimer epitope. Additionally, EDIII is the major target of neutralization antibodies. The envelope protein is an important target for research to develop vaccine candidates and antiviral therapeutics. This review summarizes the structures and functions of ED I/II/III, and provides practical applications for the three domains, with the ultimate goal of implementing strategies to utilize the envelope protein against flavivirus infections, thus achieving better diagnostics and developing potential flavivirus therapeutics and vaccines.

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Structure of the dengue virus envelope protein after membrane fusion.

Yorgo Modis, Steven Ogata, David K. Clements … (2004)

Dengue virus enters a host cell when the viral envelope glycoprotein, E, binds to a receptor and responds by conformational rearrangement to the reduced pH of an endosome. The conformational change induces fusion of viral and host-cell membranes. A three-dimensional structure of the soluble E ectodomain (sE) in its trimeric, postfusion state reveals striking differences from the dimeric, prefusion form. The elongated trimer bears three 'fusion loops' at one end, to insert into the host-cell membrane. Their structure allows us to model directly how these fusion loops interact with a lipid bilayer. The protein folds back on itself, directing its carboxy terminus towards the fusion loops. We propose a fusion mechanism driven by essentially irreversible conformational changes in E and facilitated by fusion-loop insertion into the outer bilayer leaflet. Specific features of the folded-back structure suggest strategies for inhibiting flavivirus entry.

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A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus.

Wanwisa Dejnirattisai, Wiyada Wongwiwat, Sunpetchuda Supasa … (2015)

Dengue is a rapidly emerging, mosquito-borne viral infection, with an estimated 400 million infections occurring annually. To gain insight into dengue immunity, we characterized 145 human monoclonal antibodies (mAbs) and identified a previously unknown epitope, the envelope dimer epitope (EDE), that bridges two envelope protein subunits that make up the 90 repeating dimers on the mature virion. The mAbs to EDE were broadly reactive across the dengue serocomplex and fully neutralized virus produced in either insect cells or primary human cells, with 50% neutralization in the low picomolar range. Our results provide a path to a subunit vaccine against dengue virus and have implications for the design and monitoring of future vaccine trials in which the induction of antibody to the EDE should be prioritized.

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Recognition determinants of broadly neutralizing human antibodies against dengue viruses.

Alexander Rouvinski, Pablo Guardado-Calvo, Giovanna Barba-Spaeth … (2015)

Dengue disease is caused by four different flavivirus serotypes, which infect 390 million people yearly with 25% symptomatic cases and for which no licensed vaccine is available. Recent phase III vaccine trials showed partial protection, and in particular no protection for dengue virus serotype 2 (refs 3, 4). Structural studies so far have characterized only epitopes recognized by serotype-specific human antibodies. We recently isolated human antibodies potently neutralizing all four dengue virus serotypes. Here we describe the X-ray structures of four of these broadly neutralizing antibodies in complex with the envelope glycoprotein E from dengue virus serotype 2, revealing that the recognition determinants are at a serotype-invariant site at the E-dimer interface, including the exposed main chain of the E fusion loop and the two conserved glycan chains. This 'E-dimer-dependent epitope' is also the binding site for the viral glycoprotein prM during virus maturation in the secretory pathway of the infected cell, explaining its conservation across serotypes and highlighting an Achilles' heel of the virus with respect to antibody neutralization. These findings will be instrumental for devising novel immunogens to protect simultaneously against all four serotypes of dengue virus.

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Journal

Journal ID (nlm-ta): Viruses

Journal ID (iso-abbrev): Viruses

Journal ID (publisher-id): viruses

Title: Viruses

Publisher: MDPI

ISSN (Electronic): 1999-4915

Publication date (Electronic): 13 November 2017

Publication date Collection: November 2017

Volume: 9

Issue: 11

Electronic Location Identifier: 338

Affiliations

[1 ]Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China; zhangxc923@ 123456163.com (X.Z.); shenhaoyue0724@ 123456163.com (H.S.); mshwang@ 123456163.com (M.W.)

[2 ]Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China

[3 ]Key Laboratory of Animal Disease and Human Health of Sichuan Province, Wenjiang District, Chengdu 611130, China; yinzhongq@ 123456163.com

Author notes

[* ]Correspondence: jiary@ 123456sicau.edu.cn (R.J.); chenganchun@ 123456vip.163.com (A.C.); Tel: +86-28-8629-1176 (R.J.)

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Anchun Cheng https://orcid.org/0000-0001-6093-353X

Article

Publisher ID: viruses-09-00338

DOI: 10.3390/v9110338

PMC ID: 5707545

PubMed ID: 29137162

SO-VID: 2e3fc117-0022-402b-93a1-f6d186a49982

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Structures and Functions of the Envelope Glycoprotein in Flavivirus Infections

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Zika Virus

Most cited references 96

Structure of the dengue virus envelope protein after membrane fusion.

A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus.

Recognition determinants of broadly neutralizing human antibodies against dengue viruses.

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