A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission.
Thomas G FlowerYoshinori TakahashiArpa HudaitKevin M RoseNicholas TjahjonoAlexander J PakAdam L YokomXinwen LiangHong-Gang WangFadila BouamrGregory A VothJames H HurleyPublished in: Nature structural & molecular biology (2020)
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.
Keyphrases
- antiretroviral therapy
- hiv positive
- hiv infected
- hiv testing
- human immunodeficiency virus
- hepatitis c virus
- hiv aids
- men who have sex with men
- endothelial cells
- molecular dynamics
- south africa
- stem cells
- dna damage
- oxidative stress
- machine learning
- cell cycle
- electronic health record
- deep learning
- solid state
- disease virus