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

TG Flower and Y Takahashi and A Hudait and K Rose and N Tjahjono and AJ Pak and AL Yokom and XW Liang and HG Wang and F Bouamr and GA Voth and JH Hurley, NATURE STRUCTURAL & MOLECULAR BIOLOGY, 27, 570-+ (2020).

DOI: 10.1038/s41594-020-0426-4

A crystal structure of human ESCRT-I headpiece reveals a helical assembly that is required for autophagosome closure and HIV-1 release in cells. The work suggests that ESCRT-I assembly templates ESCRT-III assembly for membrane scission. 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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