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; Peijun Zhang

doi:10.1038/ncomms10714

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, Peijun Zhang

Department of Physiology and Cell Biology

Ben-Gurion University of the Negev

Research output: Contribution to journal › Article › peer-review

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-A 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.

Original language	American English
Article number	10714
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10714
State	Published - 1 Jan 2016

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ncomms10714

Cite this

Liu, C., Perilla, J. R., Ning, J., Lu, M., Hou, G., Ramalho, R., Himes, B. A., Zhao, G., Bedwell, G. J., Byeon, I. J., Ahn, J., Gronenborn, A. M., Prevelige, P. E., Rousso, I., Aiken, C., Polenova, T., Schulten, K., & Zhang, P. (2016). Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site. Nature Communications, 7, Article 10714. https://doi.org/10.1038/ncomms10714

@article{c322cbe0fe8845ff940ae2a672be49da,

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-A 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.",

author = "Chuang Liu and Perilla, \{Juan R.\} and Jiying Ning and Manman Lu and Guangjin Hou and Ruben Ramalho and Himes, \{Benjamin A.\} and Gongpu Zhao and Bedwell, \{Gregory J.\} and Byeon, \{In Ja\} and Jinwoo Ahn and Gronenborn, \{Angela M.\} and Prevelige, \{Peter E.\} and Itay Rousso and Christopher Aiken and Tatyana Polenova and Klaus Schulten and Peijun Zhang",

note = "Funding Information: We thank Dr Teresa Brosenitsch for critical reading of the manuscript. This work was supported by the National Institutes of Health NIGMS Grant R01GM085043 (P.Z.), P50GM082251 (A.M.G.), P41GM104601 (K.S.), R01GM067887 (K.S.), the National Science Foundation (NSF) PHY-1430124 (K.S.) and the Israeli Science Foundation (grant 1115/13) (I.R.). Large-scale MD simulations were performed on the Blue Waters supercomputer, financed by the NSF (awards OCI-0725070 and ACI-1238993), and on Titan Supercomputers, supported by the Department of Energy (Contract DE-AC05-00OR22725). T.P. acknowledges the support of the NSF CHE0959496 grant, for acquisition of an 850 MHz NMR spectrometer, and the NIGMS P30GM110758 grant for support of core instrumentation infrastructure at the University of Delaware.",

year = "2016",

month = jan,

day = "1",

doi = "10.1038/ncomms10714",

language = "American English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

TY - JOUR

T1 - Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site

AU - Liu, Chuang

AU - Perilla, Juan R.

AU - Ning, Jiying

AU - Lu, Manman

AU - Hou, Guangjin

AU - Ramalho, Ruben

AU - Himes, Benjamin A.

AU - Zhao, Gongpu

AU - Bedwell, Gregory J.

AU - Byeon, In Ja

AU - Ahn, Jinwoo

AU - Gronenborn, Angela M.

AU - Prevelige, Peter E.

AU - Rousso, Itay

AU - Aiken, Christopher

AU - Polenova, Tatyana

AU - Schulten, Klaus

AU - Zhang, Peijun

N1 - Funding Information: We thank Dr Teresa Brosenitsch for critical reading of the manuscript. This work was supported by the National Institutes of Health NIGMS Grant R01GM085043 (P.Z.), P50GM082251 (A.M.G.), P41GM104601 (K.S.), R01GM067887 (K.S.), the National Science Foundation (NSF) PHY-1430124 (K.S.) and the Israeli Science Foundation (grant 1115/13) (I.R.). Large-scale MD simulations were performed on the Blue Waters supercomputer, financed by the NSF (awards OCI-0725070 and ACI-1238993), and on Titan Supercomputers, supported by the Department of Energy (Contract DE-AC05-00OR22725). T.P. acknowledges the support of the NSF CHE0959496 grant, for acquisition of an 850 MHz NMR spectrometer, and the NIGMS P30GM110758 grant for support of core instrumentation infrastructure at the University of Delaware.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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-A 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.

AB - 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-A 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.

UR - http://www.scopus.com/inward/record.url?scp=84963978172&partnerID=8YFLogxK

U2 - 10.1038/ncomms10714

DO - 10.1038/ncomms10714

M3 - Article

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10714

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this