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Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):E9401-E9410. doi: 10.1073/pnas.1811237115. Epub 2018 Sep 14.

High-resolution structures of HIV-1 Gag cleavage mutants determine structural switch for virus maturation.

Author information

1
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
2
Molecular Medicine Partnership Unit, EMBL and Universitätsklinikum Heidelberg, 69117 Heidelberg, Germany.
3
Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland.
4
Structural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
5
Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.
6
Department of Infectious Diseases, Virology, Universitätsklinikum Heidelberg, 69120 Heidelberg, Germany.
7
Molecular Medicine Partnership Unit, EMBL and Universitätsklinikum Heidelberg, 69117 Heidelberg, Germany; hans-georg.kraeusslich@med.uni-heidelberg.de jbriggs@mrc-lmb.cam.ac.uk.
8
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany; hans-georg.kraeusslich@med.uni-heidelberg.de jbriggs@mrc-lmb.cam.ac.uk.

Abstract

HIV-1 maturation occurs via multiple proteolytic cleavages of the Gag polyprotein, causing rearrangement of the virus particle required for infectivity. Cleavage results in beta-hairpin formation at the N terminus of the CA (capsid) protein and loss of a six-helix bundle formed by the C terminus of CA and the neighboring SP1 peptide. How individual cleavages contribute to changes in protein structure and interactions, and how the mature, conical capsid forms, are poorly understood. Here, we employed cryoelectron tomography to determine morphology and high-resolution CA lattice structures for HIV-1 derivatives in which Gag cleavage sites are mutated. These analyses prompt us to revise current models for the crucial maturation switch. Unlike previously proposed, cleavage on either terminus of CA was sufficient, in principle, for lattice maturation, while complete processing was needed for conical capsid formation. We conclude that destabilization of the six-helix bundle, rather than beta-hairpin formation, represents the main determinant of structural maturation.

KEYWORDS:

capsid; cryoelectron tomography; maturation; retrovirus; subtomogram averaging

PMID:
30217893
PMCID:
PMC6176557
DOI:
10.1073/pnas.1811237115
[Indexed for MEDLINE]
Free PMC Article

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