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Protease Cleavage Leads to Formation of Mature Trimer Interface in HIV-1 Capsid

Meng, X and Zhao, G and Yufenyuy, E and Ke, D and Ning, J and DeLucia, M and Ahn, J and Gronenborn, AM and Aiken, C and Zhang, P (2012) Protease Cleavage Leads to Formation of Mature Trimer Interface in HIV-1 Capsid. PLoS Pathogens, 8 (8). ISSN 1553-7366

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Abstract

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. © 2012 Meng et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Meng, X
Zhao, Ggoz1@pitt.eduGOZ1
Yufenyuy, E
Ke, D
Ning, Jjin7@pitt.eduJIN7
DeLucia, Mmld80@pitt.eduMLD80
Ahn, Jjia12@pitt.eduJIA12
Gronenborn, AMamg100@pitt.eduAMG100
Aiken, C
Zhang, PPEZ7@pitt.eduPEZ7
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorYoung, John A. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 August 2012
Date Type: Publication
Journal or Publication Title: PLoS Pathogens
Volume: 8
Number: 8
DOI or Unique Handle: 10.1371/journal.ppat.1002886
Schools and Programs: School of Medicine > Structural Biology
Refereed: Yes
ISSN: 1553-7366
Other ID: NLM PMC3426514
PubMed Central ID: PMC3426514
PubMed ID: 22927821
Date Deposited: 18 Oct 2012 21:04
Last Modified: 04 Feb 2019 15:58
URI: http://d-scholarship.pitt.edu/id/eprint/15891

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