Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site

Chuang Liu, Juan R. Perilla, Jiying Ning, Manman Lu, Guangjin Hou, Ruben Ramalho, Benjamin A. Himes, Gongpu Zhao, Gregory J. Bedwell, In-Ja Byeon, Jinwoo Ahn, Angela M. Gronenborn, Peter E. Prevelige, Itay Rousso, Christopher Aiken, Tatyana Polenova, Klaus Schulten () and Peijun Zhang ()
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Chuang Liu: University of Pittsburgh School of Medicine
Juan R. Perilla: University of Illinois at Urbana-Champaign
Jiying Ning: University of Pittsburgh School of Medicine
Manman Lu: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine
Guangjin Hou: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine
Ruben Ramalho: Ben-Gurion University of the Negev
Benjamin A. Himes: University of Pittsburgh School of Medicine
Gongpu Zhao: University of Pittsburgh School of Medicine
Gregory J. Bedwell: University of Alabama at Birmingham
In-Ja Byeon: University of Pittsburgh School of Medicine
Jinwoo Ahn: University of Pittsburgh School of Medicine
Angela M. Gronenborn: University of Pittsburgh School of Medicine
Peter E. Prevelige: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine
Itay Rousso: Ben-Gurion University of the Negev
Christopher Aiken: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine
Tatyana Polenova: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine
Klaus Schulten: University of Illinois at Urbana-Champaign
Peijun Zhang: University of Pittsburgh School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract The host cell factor cyclophilin A (CypA) interacts directly with the HIV-1 capsid and regulates viral infectivity. Although the crystal structure of CypA in complex with the N-terminal domain of the HIV-1 capsid protein (CA) has been known for nearly two decades, how CypA interacts with the viral capsid and modulates HIV-1 infectivity remains unclear. We determined the cryoEM structure of CypA in complex with the assembled HIV-1 capsid at 8-Å resolution. The structure exhibits a distinct CypA-binding pattern in which CypA selectively bridges the two CA hexamers along the direction of highest curvature. EM-guided all-atom molecular dynamics simulations and solid-state NMR further reveal that the CypA-binding pattern is achieved by single-CypA molecules simultaneously interacting with two CA subunits, in different hexamers, through a previously uncharacterized non-canonical interface. These results provide new insights into how CypA stabilizes the HIV-1 capsid and is recruited to facilitate HIV-1 infection.

Date: 2016
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DOI: 10.1038/ncomms10714

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