Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 47, Pages 14617-14622Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1516920112
Keywords
magic angle spinning NMR; HIV-1 capsid; CA protein assemblies; escape mutations; conformational dynamics
Categories
Funding
- National Institutes of Health (NIH) National Institute of General Medical Sciences [P50 GM082251]
- National Science Foundation (NSF) [CHE0959496]
- NIH [P30GM103519, P30GM110758, 9P41GM104601, R01GM067887]
- NSF [DMR-1157490, PHY1430124, OCI-0725070, ACI-1238993]
- State of Florida
- Petascale Computational Resource Grant [ACI-1440026]
- Direct For Computer & Info Scie & Enginr
- Office of Advanced Cyberinfrastructure (OAC) [1440026] Funding Source: National Science Foundation
- Direct For Mathematical & Physical Scien
- Division Of Physics [1430124] Funding Source: National Science Foundation
- Office of Integrative Activities
- Office Of The Director [1301765] Funding Source: National Science Foundation
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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 H-1-N-15 and H-1-C-13 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.
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