期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 27, 期 6, 页码 570-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41594-020-0426-4
关键词
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资金
- NIH [R37 AI112442, R01 GM127954, R01 GM128507, F32 AI150477]
- National Institutes of Health [R01 GM124149, P30 GM124169]
- Plexxikon Inc.
- Integrated Diffraction Analysis Technologies program of the US Department of Energy Office of Biological and Environmental Research
- US Department of Energy, Office of Basic Energy Sciences [DE-AC02-05CH11231]
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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