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A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission

View ORCID ProfileThomas G. Flower, View ORCID ProfileYoshinori Takahashi, Arpa Hudait, Kevin Rose, Nicholas Tjahjono, Alexander Pak, View ORCID ProfileAdam L. Yokom, Xinwen Liang, View ORCID ProfileHong-Gang Wang, Fadila Bouamr, Gregory A. Voth, View ORCID ProfileJames H. Hurley
doi: https://doi.org/10.1101/2020.01.31.927327
Thomas G. Flower
Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA
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  • ORCID record for Thomas G. Flower
Yoshinori Takahashi
Department of Pediatrics, Penn State College of Medicine, Hershey, PA 17033, USA
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  • ORCID record for Yoshinori Takahashi
Arpa Hudait
Department of Chemistry, James Franck Institute, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, USA
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Kevin Rose
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Building 4, Room B1-33, 4 Center Drive, MSC 0460, Bethesda, MD 20892, USA
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Nicholas Tjahjono
Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA
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Alexander Pak
Department of Chemistry, James Franck Institute, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, USA
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Adam L. Yokom
Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA
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Xinwen Liang
Department of Pediatrics, Penn State College of Medicine, Hershey, PA 17033, USA
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Hong-Gang Wang
Department of Pediatrics, Penn State College of Medicine, Hershey, PA 17033, USA
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  • ORCID record for Hong-Gang Wang
Fadila Bouamr
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Building 4, Room B1-33, 4 Center Drive, MSC 0460, Bethesda, MD 20892, USA
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Gregory A. Voth
Department of Chemistry, James Franck Institute, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, USA
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James H. Hurley
Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USAMolecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
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  • For correspondence: jimhurley@berkeley.edu
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Abstract

The ESCRT complexes drive membrane scission in HIV-1 release, autophagosome closure, MVB biogenesis, cytokinesis, and other cell processes. ESCRT-I is the most upstream complex and bridges the system to HIV-1 Gag in virus release. The crystal structure of the headpiece of human ESCRT-I comprising TSG101:VPS28:VPS37B:MVB12A was determined, revealing an ESCRT-I helical assembly with a 12 molecule repeat. Electron microscopy confirmed that ESCRT-I subcomplexes form helical filaments in solution. Mutation of VPS28 helical interface residues blocks filament formation in vitro and autophagosome closure and HIV-1 release in human cells. Coarse grained simulations of ESCRT assembly at HIV-1 budding sites suggest that formation of a 12-membered ring of ESCRT-I molecules is a geometry-dependent checkpoint during late stages of Gag assembly and HIV-1 budding, and templates ESCRT-III assembly for membrane scission. These data show that ESCRT-I is not merely a bridging adaptor, but has an essential scaffolding and mechanical role in its own right.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted February 01, 2020.
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A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission
Thomas G. Flower, Yoshinori Takahashi, Arpa Hudait, Kevin Rose, Nicholas Tjahjono, Alexander Pak, Adam L. Yokom, Xinwen Liang, Hong-Gang Wang, Fadila Bouamr, Gregory A. Voth, James H. Hurley
bioRxiv 2020.01.31.927327; doi: https://doi.org/10.1101/2020.01.31.927327
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A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission
Thomas G. Flower, Yoshinori Takahashi, Arpa Hudait, Kevin Rose, Nicholas Tjahjono, Alexander Pak, Adam L. Yokom, Xinwen Liang, Hong-Gang Wang, Fadila Bouamr, Gregory A. Voth, James H. Hurley
bioRxiv 2020.01.31.927327; doi: https://doi.org/10.1101/2020.01.31.927327

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