Multidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization

DOI: 10.1038/s41467-023-41197-7

Authors: Anna T. Gres (University of Missouri) , Karen A. Kirby (Emory University School of Medicine; Children’s Healthcare of Atlanta) , William M. Mcfadden (Emory University School of Medicine) , Haijuan Du (Emory University School of Medicine) , Dandan Liu (University of Missouri; University of Missouri School of Medicine) , Chaoyi Xu (University of Delaware) , Alexander J. Bryer (University of Delaware) , Juan R. Perilla (University of Delaware; University of Illinois at Urbana-Champaign) , Jiong Shi (Vanderbilt University Medical Center) , Christopher Aiken (Vanderbilt University Medical Center) , Xiaofeng Fu (University of Pittsburgh) , Peijun Zhang (University of Pittsburgh; University of Oxford; Diamond Light Source) , Ashwanth C. Francis (Florida State University; Emory University School of Medicine) , Gregory B. Melikyan (Children’s Healthcare of Atlanta; Emory University School of Medicine) , Stefan G. Sarafianos (Emory University School of Medicine; Children’s Healthcare of Atlanta; University of Missouri School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 14

State: Published (Approved)
Published: September 2023

Abstract: HIV-1 capsid (CA) stability is important for viral replication. E45A and P38A mutations enhance and reduce core stability, thus impairing infectivity. Second-site mutations R132T and T216I rescue infectivity. Capsid lattice stability was studied by solving seven crystal structures (in native background), including P38A, P38A/T216I, E45A, E45A/R132T CA, using molecular dynamics simulations of lattices, cryo-electron microscopy of assemblies, time-resolved imaging of uncoating, biophysical and biochemical characterization of assembly and stability. We report pronounced and subtle, short- and long-range rearrangements: (1) A38 destabilized hexamers by loosening interactions between flanking CA protomers in P38A but not P38A/T216I structures. (2) Two E45A structures showed unexpected stabilizing CANTD-CANTD inter-hexamer interactions, variable R18-ring pore sizes, and flipped N-terminal β-hairpin. (3) Altered conformations of E45Aa α9-helices compared to WT, E45A/R132T, WTPF74, WTNup153, and WTCPSF6 decreased PF74, CPSF6, and Nup153 binding, and was reversed in E45A/R132T. (4) An environmentally sensitive electrostatic repulsion between E45 and D51 affected lattice stability, flexibility, ion and water permeabilities, electrostatics, and recognition of host factors.

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses

Subject Areas: Biology and Bio-materials, Chemistry

Facility: 23 ID-B, 23 ID-D at APS; 4.2.2 at ALS

Added On: 27/09/2023 14:33

Documents:
s41467-023-41197-7.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Biophysics Life Sciences & Biotech

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