期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 24, 页码 13699-13707出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1920896117
关键词
adenovirus; DNA virus; virus assembly; virus entry; virus maturation
资金
- Spanish State Research Agency [BFU2016-74868-P]
- European Regional Development Fund
- Spanish Ministry of Economy, Industry and Competitiveness (the Spanish Adenovirus Network, AdenoNet) [BIO2015-68990-REDT]
- Spanish Adenovirus Network [FIS2017-89549-R]
- Maria de Maeztu Program for Units of Excellence in RD [MDM-2014-0377, FIS2017-90701-REDT]
- National Institutes of Health [CA122677, AI102577]
- Swiss National Science Foundation [SNSF 31003A_179256/1]
- Swiss National Science Foundation program Sinergia [CRSII5_170929/1, BFU2015-70052R]
- (European Regional Development Fund)
- Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias
- Spanish Institute of Health Carlos III - Spanish State Research Agency
- La Caixa Foundation
- Swiss National Science Foundation (SNF) [CRSII5_170929] Funding Source: Swiss National Science Foundation (SNF)
Adenovirus minor coat protein VI contains a membrane-disrupting peptide that is inactive when VI is bound to hexon trimers. Protein VI must be released during entry to ensure endosome escape. Hexon:VI stoichiometry has been uncertain, and only fragments of VI have been identified in the virion structure. Recent findings suggest an unexpected relationship between VI and the major core protein, VII. According to the high-resolution structure of the mature virion, VI and VII may compete for the same binding site in hexon; and noninfectious human adenovirus type 5 particles assembled in the absence of VII (Ad5-VII-) are deficient in proteolytic maturation of protein VI and endosome escape. Here we show that Ad5-VII- particles are trapped in the endosome because they fail to increase VI exposure during entry. This failure was not due to increased particle stability, because capsid disruption happened at lower thermal or mechanical stress in Ad5-VII- compared to wild-type (Ad5-wt) particles. Cryoelectron microscopy difference maps indicated that VII can occupy the same binding pocket as VI in all hexon monomers, strongly arguing for binding competition. In the Ad5-VII- map, density corresponding to the immature amino-terminal region of VI indicates that in the absence of VII the lytic peptide is trapped inside the hexon cavity, and clarifies the hexon:VI stoichiometry conundrum. We propose a model where dynamic competition between proteins VI and VII for hexon binding facilitates the complete maturation of VI, and is responsible for releasing the lytic protein from the hexon cavity during entry and stepwise uncoating.
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