Protease cleavage leads to formation of mature trimer interface in HIV-1 capsid.

During retrovirus particle maturation, the assembled Gag polyprotein is cleaved by the viral protease into matrix (MA), capsid (CA), and nucleocapsid (NC) proteins. To form the mature viral capsid, CA rearranges, resulting in a lattice composed of hexameric and pentameric CA units. Recent structural...

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Autores principales:	Xin Meng, Gongpu Zhao, Ernest Yufenyuy, Danxia Ke, Jiying Ning, Maria Delucia, Jinwoo Ahn, Angela M Gronenborn, Christopher Aiken, Peijun Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/4ba7f10758c64024af642a710629eb87
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spelling	oai:doaj.org-article:4ba7f10758c64024af642a710629eb872021-11-18T06:04:02ZProtease cleavage leads to formation of mature trimer interface in HIV-1 capsid.1553-73661553-737410.1371/journal.ppat.1002886https://doaj.org/article/4ba7f10758c64024af642a710629eb872012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22927821/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374During retrovirus particle maturation, the assembled Gag polyprotein is cleaved by the viral protease into matrix (MA), capsid (CA), and nucleocapsid (NC) proteins. To form the mature viral capsid, CA rearranges, resulting in a lattice composed of hexameric and pentameric CA units. Recent structural studies of assembled HIV-1 CA revealed several inter-subunit interfaces in the capsid lattice, including a three-fold interhexamer interface that is critical for proper capsid stability. Although a general architecture of immature particles has been provided by cryo-electron tomographic studies, the structural details of the immature particle and the maturation pathway remain unknown. Here, we used cryo-electron microscopy (cryoEM) to determine the structure of tubular assemblies of the HIV-1 CA-SP1-NC protein. Relative to the mature assembled CA structure, we observed a marked conformational difference in the position of the CA-CTD relative to the NTD in the CA-SP1-NC assembly, involving the flexible hinge connecting the two domains. This difference was verified via engineered disulfide crosslinking, revealing that inter-hexamer contacts, in particular those at the pseudo three-fold axis, are altered in the CA-SP1-NC assemblies compared to the CA assemblies. Results from crosslinking analyses of mature and immature HIV-1 particles containing the same Cys substitutions in the Gag protein are consistent with these findings. We further show that cleavage of preassembled CA-SP1-NC by HIV-1 protease in vitro leads to release of SP1 and NC without disassembly of the lattice. Collectively, our results indicate that the proteolytic cleavage of Gag leads to a structural reorganization of the polypeptide and creates the three-fold interhexamer interface, important for the formation of infectious HIV-1 particles.Xin MengGongpu ZhaoErnest YufenyuyDanxia KeJiying NingMaria DeluciaJinwoo AhnAngela M GronenbornChristopher AikenPeijun ZhangPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 8, p e1002886 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Xin Meng Gongpu Zhao Ernest Yufenyuy Danxia Ke Jiying Ning Maria Delucia Jinwoo Ahn Angela M Gronenborn Christopher Aiken Peijun Zhang Protease cleavage leads to formation of mature trimer interface in HIV-1 capsid.
description	During retrovirus particle maturation, the assembled Gag polyprotein is cleaved by the viral protease into matrix (MA), capsid (CA), and nucleocapsid (NC) proteins. To form the mature viral capsid, CA rearranges, resulting in a lattice composed of hexameric and pentameric CA units. Recent structural studies of assembled HIV-1 CA revealed several inter-subunit interfaces in the capsid lattice, including a three-fold interhexamer interface that is critical for proper capsid stability. Although a general architecture of immature particles has been provided by cryo-electron tomographic studies, the structural details of the immature particle and the maturation pathway remain unknown. Here, we used cryo-electron microscopy (cryoEM) to determine the structure of tubular assemblies of the HIV-1 CA-SP1-NC protein. Relative to the mature assembled CA structure, we observed a marked conformational difference in the position of the CA-CTD relative to the NTD in the CA-SP1-NC assembly, involving the flexible hinge connecting the two domains. This difference was verified via engineered disulfide crosslinking, revealing that inter-hexamer contacts, in particular those at the pseudo three-fold axis, are altered in the CA-SP1-NC assemblies compared to the CA assemblies. Results from crosslinking analyses of mature and immature HIV-1 particles containing the same Cys substitutions in the Gag protein are consistent with these findings. We further show that cleavage of preassembled CA-SP1-NC by HIV-1 protease in vitro leads to release of SP1 and NC without disassembly of the lattice. Collectively, our results indicate that the proteolytic cleavage of Gag leads to a structural reorganization of the polypeptide and creates the three-fold interhexamer interface, important for the formation of infectious HIV-1 particles.
format	article
author	Xin Meng Gongpu Zhao Ernest Yufenyuy Danxia Ke Jiying Ning Maria Delucia Jinwoo Ahn Angela M Gronenborn Christopher Aiken Peijun Zhang
author_facet	Xin Meng Gongpu Zhao Ernest Yufenyuy Danxia Ke Jiying Ning Maria Delucia Jinwoo Ahn Angela M Gronenborn Christopher Aiken Peijun Zhang
author_sort	Xin Meng
title	Protease cleavage leads to formation of mature trimer interface in HIV-1 capsid.
title_short	Protease cleavage leads to formation of mature trimer interface in HIV-1 capsid.
title_full	Protease cleavage leads to formation of mature trimer interface in HIV-1 capsid.
title_fullStr	Protease cleavage leads to formation of mature trimer interface in HIV-1 capsid.
title_full_unstemmed	Protease cleavage leads to formation of mature trimer interface in HIV-1 capsid.
title_sort	protease cleavage leads to formation of mature trimer interface in hiv-1 capsid.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/4ba7f10758c64024af642a710629eb87
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Protease cleavage leads to formation of mature trimer interface in HIV-1 capsid.

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