Intrinsic curvature of the HIV-1 CA hexamer underlies capsid topology and interaction with cyclophilin A

DOI: 10.1038/s41594-020-0467-8

Authors: Tao Ni (Wellcome Centre for Human Genetics, University of Oxford) , Samuel Gerard (Wellcome Centre for Human Genetics, University of Oxford) , Gongpu Zhao (University of Pittsburgh School of Medicine) , Kyle Dent (Diamond Light Source) , Jiying Ning (University of Pittsburgh School of Medicine) , Jing Zhou (Vanderbilt University Medical Center) , Jiong Shi (Vanderbilt University Medical Center) , Jordan Anderson-Daniels (Vanderbilt University Medical Center) , Wen Li (Harvard Medical School; Dana-Farber Cancer Institute) , Sooin Jang (Harvard Medical School; Dana-Farber Cancer Institute) , Alan N. Engelman (Harvard Medical School; Dana-Farber Cancer Institute) , Christopher Aiken (Vanderbilt University Medical Center) , Peijun Zhang (Diamond Light Source; Wellcome Centre for Human Genetics, University of Oxford: University of Pittsburgh School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 5

State: Published (Approved)
Published: August 2020
Diamond Proposal Number(s): 14856 , 21004

Abstract: The mature retrovirus capsid consists of a variably curved lattice of capsid protein (CA) hexamers and pentamers. High-resolution structures of the curved assembly, or in complex with host factors, have not been available. By devising cryo-EM methodologies for exceedingly flexible and pleomorphic assemblies, we have determined cryo-EM structures of apo-CA hexamers and in complex with cyclophilin A (CypA) at near-atomic resolutions. The CA hexamers are intrinsically curved, flexible and asymmetric, revealing the capsomere and not the previously touted dimer or trimer interfaces as the key contributor to capsid curvature. CypA recognizes specific geometries of the curved lattice, simultaneously interacting with three CA protomers from adjacent hexamers via two noncanonical interfaces, thus stabilizing the capsid. By determining multiple structures from various helical symmetries, we further revealed the essential plasticity of the CA molecule, which allows formation of continuously curved conical capsids and the mechanism of capsid pattern sensing by CypA.

Journal Keywords: Cryoelectron microscopy; Electron microscopy; Microbiology; Structural biology; Virology

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond , Krios IV-Titan Krios IV at Diamond

Added On: 10/08/2020 11:22

Discipline Tags:

Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)