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

Gres, Anna T.; Kirby, Karen A.; McFadden, William M.; Du, Haijuan; Liu, Dandan; Xu, Chaoyi; Bryer, Alexander J.; Perilla, Juan R.; Shi, Jiong; Aiken, Christopher; Fu, Xiaofeng; Zhang, Peijun; Francis, Ashwanth C.; Melikyan, Gregory B.; Sarafianos, Stefan G.

doi:10.1038/s41467-023-41197-7

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

Journal Article · 12 September 2023 · Nature Communications

DOI: https://doi.org/10.1038/s41467-023-41197-7 · OSTI ID:1999707

Gres, Anna T.; Kirby, Karen A.; McFadden, William M.; Du, Haijuan; Liu, Dandan;

;

; Shi, Jiong; Aiken, Christopher;

;

; Francis, Ashwanth C.;

; Sarafianos, Stefan G.

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 CA _NTD -CA _NTD inter-hexamer interactions, variable R18-ring pore sizes, and flipped N-terminal β-hairpin. (3) Altered conformations of E45A ^a α9-helices compared to WT, E45A/R132T, WT _PF74 , WT _Nup153 , and WT _CPSF6 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF); USDOE; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357

OSTI ID:: 1999707

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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