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

Author

Listed:
  • Anna T. Gres

    (University of Missouri
    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, School of Medicine)

  • Peijun Zhang

    (University of Pittsburgh, School of Medicine
    University of Oxford, The Henry Wellcome Building for Genomic Medicine
    Harwell Science and Innovation Campus)

  • 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)

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.

Suggested Citation

  • Anna T. Gres & Karen A. Kirby & William M. McFadden & Haijuan Du & Dandan Liu & Chaoyi Xu & Alexander J. Bryer & Juan R. Perilla & Jiong Shi & Christopher Aiken & Xiaofeng Fu & Peijun Zhang & Ashwanth, 2023. "Multidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41197-7
    DOI: 10.1038/s41467-023-41197-7
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    References listed on IDEAS

    as
    1. Robert A. Dick & Kaneil K. Zadrozny & Chaoyi Xu & Florian K. M. Schur & Terri D. Lyddon & Clifton L. Ricana & Jonathan M. Wagner & Juan R. Perilla & Barbie K. Ganser-Pornillos & Marc C. Johnson & Owen, 2018. "Inositol phosphates are assembly co-factors for HIV-1," Nature, Nature, vol. 560(7719), pages 509-512, August.
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