Electrostatic repulsion between HIV-1 capsid proteins modulates hexamer plasticity and in vitro assembly

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Structure of HIV-1 Capsid Assemblies by Cryo-electron Microscopy and Iterative Helical Real-space Reconstruction
12:38

Structure of HIV-1 Capsid Assemblies by Cryo-electron Microscopy and Iterative Helical Real-space Reconstruction

Published on: August 9, 2011

Sonia Brun1, Laurent Chaloin, Bernard Gay

  • 1Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), Université Montpellier 1, Montpellier, France.

Proteins
|May 11, 2010
PubMed

Insights

Phosphorylation of human immunodeficiency virus type 1 (HIV-1) capsid protein (CA) at specific sites impacts its assembly and core structure. Mimicking phosphorylation at S109 or S149 impairs HIV-1 assembly, while S178 phosphorylation enhances it, affecting viral infectivity.

Area of Science:

  • Virology
  • Structural Biology
  • Molecular Biology

Background:

  • The human immunodeficiency virus type 1 (HIV-1) capsid protein (CA) is crucial for viral core formation.
  • Three key phosphorylation sites (S109, S149, S178) on CA have been identified, but their functional impact remains unclear.

Purpose of the Study:

  • To investigate the effects of phosphorylation at CA's S109, S149, and S178 sites on CA hexamer organization, plasticity, and HIV-1 assembly.
  • To evaluate the biological relevance of in silico findings through in vitro and in vivo experiments.

Main Methods:

  • In silico molecular modeling to predict the impact of phosphorylation on CA hexamer structure and stability.
  • In vitro assembly assays using bacterially expressed CA mutants (S109D, S149D, S178D) mimicking constitutive phosphorylation.
  • Analysis of HIV-1 mutant core morphology and infectivity in vivo.

Main Results:

  • Constitutive negative charge at S109 or S149 significantly impaired in vitro CA assembly and led to altered core morphology in vivo.
  • S149 phosphorylation caused inter-monomer repulsions within the CA hexamer; S109 phosphorylation led to bond cleavage, destabilizing the hexamer.
  • S178 phosphorylation facilitated in vitro and in vivo CA assembly into core-like structures and enhanced hexamer stability in silico.
  • All studied HIV-1 mutants exhibited a complete loss of infectivity due to impaired proviral DNA production.

Conclusions:

  • Phosphorylation, mimicked by negative charges, modulates the assembly capacity of HIV-1 CA.
  • These phosphorylation events significantly affect the structural properties of CA hexamers and the overall HIV-1 core.
  • Phosphorylation at these sites interferes with HIV-1 core organization and the viral replicative cycle, impacting infectivity.

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