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

Journal Article · · Nature Communications
DOI:https://doi.org/10.1038/ncomms10714· OSTI ID:1623826
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [8];  [9];  [8];  [8];  [8];  [10];  [11];  [12];  [5];  [13];  [8]
  1. Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Department of Structural Biology; Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Pittsburgh Center for HIV Protein Interactions; DOE/OSTI
  2. Univ. of Illinois at Urbana-Champaign, IL (United States). Department of Physics and Beckman Institute
  3. Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Department of Structural Biology; Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Pittsburgh Center for HIV Protein Interactions
  4. Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Pittsburgh Center for HIV Protein Interactions; Univ. of Delaware, Newark, DE (United States). Department of Chemistry and Biochemistry
  5. Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Pittsburgh Center for HIV Protein Interactions; Univ. of Delaware, Newark, DE (United States). Department of Chemistry and Biochemistry
  6. Univ. of the Negev, Be’er-Sheva (Israel). Department of Physiology and Cell Biology
  7. Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Department of Structural Biology
  8. Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Department of Structural Biology; Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Pittsburgh Center for HIV Protein Interactions
  9. Univ. of Alabama, Birmingham, AL (United States). Department of Microbiology
  10. Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Pittsburgh Center for HIV Protein Interactions; Univ. of Alabama, Birmingham, AL (United States). Department of Microbiology
  11. Univ. of the Negev, Be’er-Sheva (Israel). Department of Physiology and Cell Biology
  12. Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Pittsburgh Center for HIV Protein Interactions; Vanderbilt Univ., School of Medicine, Nashville, TN (United States). Department of Pathology, Microbiology and Immunology
  13. Univ. of Illinois at Urbana-Champaign, IL (United States). Department of Physics and Beckman Institute
+ Show Author Affiliations
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.
Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC05-00OR22725
OSTI ID:
1623826
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 7; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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Cyclophilins and cyclophilin inhibitors in nidovirus replication journal September 2018
All-Atom Molecular Dynamics of Virus Capsids as Drug Targets journal May 2016
Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket journal April 2019
Functional analysis of the secondary HIV-1 capsid binding site in the host protein cyclophilin A journal April 2019
ACAP1 assembles into an unusual protein lattice for membrane deformation through multiple stages journal July 2019
Modeling the dynamics and kinetics of HIV-1 Gag during viral assembly journal April 2018
Time-Resolved Imaging of Single HIV-1 Uncoating In Vitro and in Living Cells journal June 2016
Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis journal July 2017
Toward the “unravelling” of HIV: Host cell factors involved in HIV-1 core uncoating journal October 2018
Implication of the Whitefly Bemisia tabaci Cyclophilin B Protein in the Transmission of Tomato yellow leaf curl virus journal November 2016
Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2 journal August 2018
The secrets of the stability of the HIV-1 capsid journal July 2018
Accuracy and precision of protein structures determined by magic angle spinning NMR spectroscopy: for some ‘with a little help from a friend’ journal March 2019
19F NMR relaxation studies of fluorosubstituted tryptophans journal August 2019
Proteomic Profiling of Purified Rabies Virus Particles journal August 2019
Fluorescence Biosensor for Real-Time Interaction Dynamics of Host Proteins with HIV-1 Capsid Tubes journal June 2019
Physical properties of the HIV-1 capsid from all-atom molecular dynamics simulations journal July 2017
Control of tandem isomerizations: flow-assisted reactions of o -lithiated aryl benzyl ethers journal January 2018
Dynamic design: manipulation of millisecond timescale motions on the energy landscape of cyclophilin A journal January 2020
Dynamic regulation of HIV-1 capsid interaction with the restriction factor TRIM5α identified by magic-angle spinning NMR and molecular dynamics simulations journal October 2018
Cyclophilin A allows the allosteric regulation of a structural motif in the disordered domain 2 of NS5A and thereby fine-tunes HCV RNA replication journal July 2019
Fluorescence biosensor for real-time interaction dynamics of host proteins with HIV-1 capsid tubes posted_content May 2019
Allelic variants of human genes affecting HIV intracellular life cycle and regulating immune response to HIV infection journal May 2019
Kinetics of HIV-1 capsid uncoating revealed by single-molecule analysis journal June 2018

Figures / Tables (5)

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