title: Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site.
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.
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Chuang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Physics and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Perilla
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Jiying
authors.initials: J
authors.lastname: Ning
authors.affiliation: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
authors.forename: Manman
authors.initials: M
authors.lastname: Lu
authors.affiliation: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
authors.forename: Guangjin
authors.initials: G
authors.lastname: Hou
authors.affiliation: Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Be'er-Sheva, 84105, Israel.
authors.forename: Ruben
authors.initials: R
authors.lastname: Ramalho
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Himes
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Gongpu
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham Alabama 35294, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Bedwell
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: In-Ja
authors.initials: IJ
authors.lastname: Byeon
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Gronenborn
authors.affiliation: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Department of Microbiology, University of Alabama at Birmingham, Birmingham Alabama 35294, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Prevelige
authors.affiliation: Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Be'er-Sheva, 84105, Israel.
authors.forename: Itay
authors.initials: I
authors.lastname: Rousso
authors.affiliation: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Aiken
authors.affiliation: Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Polenova
authors.affiliation: Department of Physics and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Peijun
authors.initials: P
authors.lastname: Zhang
mesh_terms: D036022:Capsid Proteins / Q000378:metabolism*; D020134:Catalytic Domain; D003198:Computer Simulation; D021984:Cyclophilin A / Q000494:pharmacology*; D004926:Escherichia coli / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D015497:HIV-1; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D019065:Virus Assembly
chemical_list: D036022:Capsid Proteins; D021984:Cyclophilin A