Dynamic allostery governs cyclophilin A-HIV capsid interplay

Manman Lu, Guangjin Hou, Huilan Zhang, Christopher L. Suiter, Jinwoo Ahn, In Ja L. Byeon, Juan R. Perilla, Christopher J. Langmead, Ivan Hung, Peter L. Gor'kov, Zhehong Gan, William Brey, Christopher Aiken, Peijun Zhang, Klaus Schulten, Angela M. Gronenborn, Tatyana Polenova

Research output: Contribution to journalArticlepeer-review

Abstract

Host factor protein Cyclophilin A (CypA) regulates HIV-1 viral infectivity through direct interactions with the viral capsid, by an unknown mechanism. CypA can either promote or inhibit viral infection, depending on host cell type and HIV-1 capsid (CA) protein sequence. We have examined the role of conformational dynamics on the nanosecond to millisecond timescale in HIV-1 CA assemblies in the escape from CypA dependence, by magic-angle spinning (MAS) NMR and molecular dynamics (MD). Through the analysis of backbone 1H-15N and 1H-13C dipolar tensors and peak intensities from 3D MAS NMR spectra of wild-type and the A92E and G94D CypA escape mutants, we demonstrate that assembled CA is dynamic, particularly in loop regions. The CypA loop in assembled wild-type CA from two strains exhibits unprecedented mobility on the nanosecond to microsecond timescales, and the experimental NMR dipolar order parameters are in quantitative agreement with those calculated from MD trajectories. Remarkably, the CypA loop dynamics of wild-type CA HXB2 assembly is significantly attenuated upon CypA binding, and the dynamics profiles of the A92E and G94D CypA escape mutants closely resemble that of wild-type CA assembly in complex with CypA. These results suggest that CypA loop dynamics is a determining factor in HIV-1's escape from CypA dependence.

Original languageEnglish (US)
Pages (from-to)14617-14622
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number47
DOIs
StatePublished - Nov 24 2015

Keywords

  • Ca protein assemblies
  • Conformational dynamics
  • Escape mutations
  • HIV-1 capsid
  • Magic angle spinning nmr

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Dynamic allostery governs cyclophilin A-HIV capsid interplay'. Together they form a unique fingerprint.

Cite this