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, and Tatyana Polenova.
Dynamic allostery governs cyclophylin A-HIV capsid interplay.
Proceedings of the National Academy of Sciences, USA,
112:14617-14622, 2015.
(PMC: PMC4664340)
LU2015
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.
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