Transmembrane Domains of Highly Pathogenic Viral Fusion Proteins Exhibit Trimeric Association <italic toggle="yes">In Vitro</italic>

ABSTRACT Enveloped viruses require viral fusion proteins to promote fusion of the viral envelope with a target cell membrane. To drive fusion, these proteins undergo large conformational changes that must occur at the right place and at the right time. Understanding the elements which control the st...

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Autores principales:	Stacy R. Webb, Stacy E. Smith, Michael G. Fried, Rebecca Ellis Dutch
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	SARS Ebola virus fusion protein influenza rabies transmembrane domain Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3fc268089f9540189e7c174b4933e428
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spelling	oai:doaj.org-article:3fc268089f9540189e7c174b4933e4282021-11-15T15:22:14ZTransmembrane Domains of Highly Pathogenic Viral Fusion Proteins Exhibit Trimeric Association <italic toggle="yes">In Vitro</italic>10.1128/mSphere.00047-182379-5042https://doaj.org/article/3fc268089f9540189e7c174b4933e4282018-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00047-18https://doaj.org/toc/2379-5042ABSTRACT Enveloped viruses require viral fusion proteins to promote fusion of the viral envelope with a target cell membrane. To drive fusion, these proteins undergo large conformational changes that must occur at the right place and at the right time. Understanding the elements which control the stability of the prefusion state and the initiation of conformational changes is key to understanding the function of these important proteins. The construction of mutations in the fusion protein transmembrane domains (TMDs) or the replacement of these domains with lipid anchors has implicated the TMD in the fusion process. However, the structural and molecular details of the role of the TMD in these fusion events remain unclear. Previously, we demonstrated that isolated paramyxovirus fusion protein TMDs associate in a monomer-trimer equilibrium, using sedimentation equilibrium analytical ultracentrifugation. Using a similar approach, the work presented here indicates that trimeric interactions also occur between the fusion protein TMDs of Ebola virus, influenza virus, severe acute respiratory syndrome coronavirus (SARS CoV), and rabies virus. Our results suggest that TM-TM interactions are important in the fusion protein function of diverse viral families. IMPORTANCE Many important human pathogens are enveloped viruses that utilize membrane-bound glycoproteins to mediate viral entry. Factors that contribute to the stability of these glycoproteins have been identified in the ectodomain of several viral fusion proteins, including residues within the soluble ectodomain. Although it is often thought to simply act as an anchor, the transmembrane domain of viral fusion proteins has been implicated in protein stability and function as well. Here, using a biophysical approach, we demonstrated that the fusion protein transmembrane domains of several deadly pathogens—Ebola virus, influenza virus, SARS CoV, and rabies virus—self-associate. This observation across various viral families suggests that transmembrane domain interactions may be broadly relevant and serve as a new target for therapeutic development.Stacy R. WebbStacy E. SmithMichael G. FriedRebecca Ellis DutchAmerican Society for MicrobiologyarticleSARSEbola virusfusion proteininfluenzarabiestransmembrane domainMicrobiologyQR1-502ENmSphere, Vol 3, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	SARS Ebola virus fusion protein influenza rabies transmembrane domain Microbiology QR1-502
spellingShingle	SARS Ebola virus fusion protein influenza rabies transmembrane domain Microbiology QR1-502 Stacy R. Webb Stacy E. Smith Michael G. Fried Rebecca Ellis Dutch Transmembrane Domains of Highly Pathogenic Viral Fusion Proteins Exhibit Trimeric Association <italic toggle="yes">In Vitro</italic>
description	ABSTRACT Enveloped viruses require viral fusion proteins to promote fusion of the viral envelope with a target cell membrane. To drive fusion, these proteins undergo large conformational changes that must occur at the right place and at the right time. Understanding the elements which control the stability of the prefusion state and the initiation of conformational changes is key to understanding the function of these important proteins. The construction of mutations in the fusion protein transmembrane domains (TMDs) or the replacement of these domains with lipid anchors has implicated the TMD in the fusion process. However, the structural and molecular details of the role of the TMD in these fusion events remain unclear. Previously, we demonstrated that isolated paramyxovirus fusion protein TMDs associate in a monomer-trimer equilibrium, using sedimentation equilibrium analytical ultracentrifugation. Using a similar approach, the work presented here indicates that trimeric interactions also occur between the fusion protein TMDs of Ebola virus, influenza virus, severe acute respiratory syndrome coronavirus (SARS CoV), and rabies virus. Our results suggest that TM-TM interactions are important in the fusion protein function of diverse viral families. IMPORTANCE Many important human pathogens are enveloped viruses that utilize membrane-bound glycoproteins to mediate viral entry. Factors that contribute to the stability of these glycoproteins have been identified in the ectodomain of several viral fusion proteins, including residues within the soluble ectodomain. Although it is often thought to simply act as an anchor, the transmembrane domain of viral fusion proteins has been implicated in protein stability and function as well. Here, using a biophysical approach, we demonstrated that the fusion protein transmembrane domains of several deadly pathogens—Ebola virus, influenza virus, SARS CoV, and rabies virus—self-associate. This observation across various viral families suggests that transmembrane domain interactions may be broadly relevant and serve as a new target for therapeutic development.
format	article
author	Stacy R. Webb Stacy E. Smith Michael G. Fried Rebecca Ellis Dutch
author_facet	Stacy R. Webb Stacy E. Smith Michael G. Fried Rebecca Ellis Dutch
author_sort	Stacy R. Webb
title	Transmembrane Domains of Highly Pathogenic Viral Fusion Proteins Exhibit Trimeric Association <italic toggle="yes">In Vitro</italic>
title_short	Transmembrane Domains of Highly Pathogenic Viral Fusion Proteins Exhibit Trimeric Association <italic toggle="yes">In Vitro</italic>
title_full	Transmembrane Domains of Highly Pathogenic Viral Fusion Proteins Exhibit Trimeric Association <italic toggle="yes">In Vitro</italic>
title_fullStr	Transmembrane Domains of Highly Pathogenic Viral Fusion Proteins Exhibit Trimeric Association <italic toggle="yes">In Vitro</italic>
title_full_unstemmed	Transmembrane Domains of Highly Pathogenic Viral Fusion Proteins Exhibit Trimeric Association <italic toggle="yes">In Vitro</italic>
title_sort	transmembrane domains of highly pathogenic viral fusion proteins exhibit trimeric association <italic toggle="yes">in vitro</italic>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/3fc268089f9540189e7c174b4933e428
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Transmembrane Domains of Highly Pathogenic Viral Fusion Proteins Exhibit Trimeric Association <italic toggle="yes">In Vitro</italic>

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