An Intrinsically Disordered Region of the Adenovirus Capsid Is Implicated in Neutralization by Human Alpha Defensin 5

Human α-defensins are proteins of the innate immune system that suppress viral and bacterial infections by multiple mechanisms including membrane disruption. For viruses that lack envelopes, such as human adenovirus (HAdV), other, less well defined, mechanisms must be involved. A previous structural...

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Main Authors:	Flatt, Justin W., Kim, Robert, Smith, Jason G., Nemerow, Glen R., Stewart, Phoebe L.
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631211/

id	pubmed-3631211
recordtype	oai_dc
spelling	pubmed-36312112013-04-25 An Intrinsically Disordered Region of the Adenovirus Capsid Is Implicated in Neutralization by Human Alpha Defensin 5 Flatt, Justin W. Kim, Robert Smith, Jason G. Nemerow, Glen R. Stewart, Phoebe L. Research Article Human α-defensins are proteins of the innate immune system that suppress viral and bacterial infections by multiple mechanisms including membrane disruption. For viruses that lack envelopes, such as human adenovirus (HAdV), other, less well defined, mechanisms must be involved. A previous structural study on the interaction of an α-defensin, human α-defensin 5 (HD5), with HAdV led to a proposed mechanism in which HD5 stabilizes the vertex region of the capsid and blocks uncoating steps required for infectivity. Studies with virus chimeras comprised of capsid proteins from sensitive and resistant serotypes supported this model. To further characterize the critical binding site, we determined subnanometer resolution cryo-electron microscopy (cryoEM) structures of HD5 complexed with both neutralization-sensitive and -resistant HAdV chimeras. Models were built for the vertex regions of these chimeras with monomeric and dimeric forms of HD5 in various initial orientations. CryoEM guided molecular dynamics flexible fitting (MDFF) was used to restrain the majority of the vertex model in well-defined cryoEM density. The RGD-containing penton base loops of both the sensitive and resistant virus chimeras are predicted to be intrinsically disordered, and little cryoEM density is observed for them. In simulations these loops from the sensitive virus chimera, interact with HD5, bridge the penton base and fiber proteins, and provides significant stabilization with a three-fold increase in the intermolecular nonbonded interactions of the vertex complex. In the case of the resistant virus chimera, simulations revealed fewer bridging interactions and reduced stabilization by HD5. This study implicates a key dynamic region in mediating a stabilizing interaction between a viral capsid and a protein of the innate immune system with potent anti-viral activity. Public Library of Science 2013-04-19 /pmc/articles/PMC3631211/ /pubmed/23620768 http://dx.doi.org/10.1371/journal.pone.0061571 Text en © 2013 Flatt et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Flatt, Justin W. Kim, Robert Smith, Jason G. Nemerow, Glen R. Stewart, Phoebe L.
spellingShingle	Flatt, Justin W. Kim, Robert Smith, Jason G. Nemerow, Glen R. Stewart, Phoebe L. An Intrinsically Disordered Region of the Adenovirus Capsid Is Implicated in Neutralization by Human Alpha Defensin 5
author_facet	Flatt, Justin W. Kim, Robert Smith, Jason G. Nemerow, Glen R. Stewart, Phoebe L.
author_sort	Flatt, Justin W.
title	An Intrinsically Disordered Region of the Adenovirus Capsid Is Implicated in Neutralization by Human Alpha Defensin 5
title_short	An Intrinsically Disordered Region of the Adenovirus Capsid Is Implicated in Neutralization by Human Alpha Defensin 5
title_full	An Intrinsically Disordered Region of the Adenovirus Capsid Is Implicated in Neutralization by Human Alpha Defensin 5
title_fullStr	An Intrinsically Disordered Region of the Adenovirus Capsid Is Implicated in Neutralization by Human Alpha Defensin 5
title_full_unstemmed	An Intrinsically Disordered Region of the Adenovirus Capsid Is Implicated in Neutralization by Human Alpha Defensin 5
title_sort	intrinsically disordered region of the adenovirus capsid is implicated in neutralization by human alpha defensin 5
description	Human α-defensins are proteins of the innate immune system that suppress viral and bacterial infections by multiple mechanisms including membrane disruption. For viruses that lack envelopes, such as human adenovirus (HAdV), other, less well defined, mechanisms must be involved. A previous structural study on the interaction of an α-defensin, human α-defensin 5 (HD5), with HAdV led to a proposed mechanism in which HD5 stabilizes the vertex region of the capsid and blocks uncoating steps required for infectivity. Studies with virus chimeras comprised of capsid proteins from sensitive and resistant serotypes supported this model. To further characterize the critical binding site, we determined subnanometer resolution cryo-electron microscopy (cryoEM) structures of HD5 complexed with both neutralization-sensitive and -resistant HAdV chimeras. Models were built for the vertex regions of these chimeras with monomeric and dimeric forms of HD5 in various initial orientations. CryoEM guided molecular dynamics flexible fitting (MDFF) was used to restrain the majority of the vertex model in well-defined cryoEM density. The RGD-containing penton base loops of both the sensitive and resistant virus chimeras are predicted to be intrinsically disordered, and little cryoEM density is observed for them. In simulations these loops from the sensitive virus chimera, interact with HD5, bridge the penton base and fiber proteins, and provides significant stabilization with a three-fold increase in the intermolecular nonbonded interactions of the vertex complex. In the case of the resistant virus chimera, simulations revealed fewer bridging interactions and reduced stabilization by HD5. This study implicates a key dynamic region in mediating a stabilizing interaction between a viral capsid and a protein of the innate immune system with potent anti-viral activity.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631211/
_version_	1611971451544403968

An Intrinsically Disordered Region of the Adenovirus Capsid Is Implicated in Neutralization by Human Alpha Defensin 5

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