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

  • Author(s): Flower, Thomas G;
  • Takahashi, Yoshinori;
  • Hudait, Arpa;
  • Rose, Kevin;
  • Tjahjono, Nicholas;
  • Pak, Alexander J;
  • Yokom, Adam L;
  • Liang, Xinwen;
  • Wang, Hong-Gang;
  • Bouamr, Fadila;
  • Voth, Gregory A;
  • Hurley, James H
  • et al.

Published Web Location

https://www.biorxiv.org/content/10.1101/2020.01.31.927327v1
No data is associated with this publication.
Abstract

The ESCRT complexes drive membrane scission in HIV-1 release, autophagosome closure, multivesicular body 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 (CG) 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; it has an essential scaffolding and mechanical role in its own right.

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