Multidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37699872.
- Also identified by DOI 10.1038/s41467-023-41197-7 and PMC identifier 10497533.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>NTD</sub>-CA<sub>NTD</sub> inter-hexamer interactions, variable R18-ring pore sizes, and flipped N-terminal β-hairpin. (3) Altered conformations of E45A<sup>a</sup> α9-helices compared to WT, E45A/R132T, WT<sub>PF74</sub>, WT<sub>Nup153</sub>, and WT<sub>CPSF6</sub> 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.
Medical subject headings
- Capsid Proteins
- HIV-1