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Organization of Upstream ESCRT Machinery at the HIV-1 Budding Site

View ORCID ProfileArpa Hudait, View ORCID ProfileJames H. Hurley, View ORCID ProfileGregory A. Voth
doi: https://doi.org/10.1101/2022.09.13.507863
Arpa Hudait
1Department of Chemistry, Chicago Center for Theoretical Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago, Chicago, IL 60637, USA
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James H. Hurley
2Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA
3California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA
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Gregory A. Voth
1Department of Chemistry, Chicago Center for Theoretical Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago, Chicago, IL 60637, USA
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  • For correspondence: gavoth@uchicago.edu
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Abstract

In the late stages of the HIV-1 life cycle, membrane localization and self-assembly of the Gag polyproteins induce membrane deformation and budding. However, release of the immature virion requires direct interaction between Gag lattice and upstream ESCRT machinery at the budding site, followed by assembly of the downstream ESCRT-III factors, culminating in membrane scission. In this work, using “bottom-up” coarse-grained (CG) molecular dynamics (MD) simulations we investigated the interactions between Gag and different upstream ESCRT components to delineate the molecular organization of proteins at the membrane neck of the HIV-1 budding site. We developed CG models of upstream ESCRT proteins and HIV-1 structural protein Gag based on experimental structural data and extensive all-atom MD simulations. We find that ESCRT-I proteins bound to the immature Gag lattice can recruit multiple copies of ESCRT-II coating the membrane neck. ESCRT-I can effectively oligomerize to higher-order complexes both in absence of ESCRT-II and when multiple copies of ESCRT-II are localized at the bud neck. The ESCRT-I/II supercomplexes observed in our simulations exhibit predominantly extended conformations. Importantly, the ESCRT-I/II supercomplex modulates the membrane mechanical properties at the budding site by decreasing the overall Gaussian curvature of membrane neck. Our findings serve to elucidate a network of interactions between the upstream ESCRT machinery, immature Gag lattice, and membrane bud neck that regulate the protein assemblies and enable bud neck constriction.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    ESCRT
    endosomal sorting complexes required for transport
    AA MD
    All-Atom Molecular Dynamics
    CG MD
    Coarse-Grained Molecular Dynamics
    RMSF
    root mean square fluctuation
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    Posted September 14, 2022.
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    Organization of Upstream ESCRT Machinery at the HIV-1 Budding Site
    Arpa Hudait, James H. Hurley, Gregory A. Voth
    bioRxiv 2022.09.13.507863; doi: https://doi.org/10.1101/2022.09.13.507863
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    Organization of Upstream ESCRT Machinery at the HIV-1 Budding Site
    Arpa Hudait, James H. Hurley, Gregory A. Voth
    bioRxiv 2022.09.13.507863; doi: https://doi.org/10.1101/2022.09.13.507863

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