期刊
CELL
卷 174, 期 3, 页码 659-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.07.004
关键词
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资金
- NIH [R01 AI 120691, P50 GM082250]
- Advanced ERC grant Anti-Virome
- DFG [SFB 1279]
- DFG SPP 1923
The HIV accessory protein Nef counteracts immune defenses by subverting coated vesicle pathways. The 3.7 angstrom cryo-EM structure of a closed trimer of the clathrin adaptor AP-1, the small GTPase Arf1, HIV-1 Nef, and the cytosolic tail of the restriction factor tetherin suggested a mechanism for inactivating tetherin by Golgi retention. The 4.3 angstrom structure of a mutant Nef-induced dimer of AP-1 showed how the closed trimer is regulated by the dileucine loop of Nef. HDX-MS and mutational analysis were used to show how cargo dynamics leads to alternative Arf1 trimerization, directing Nef targets to be either retained at the trans-Golgi or sorted to lysosomes. Phosphorylation of the NL4-3 M-Nef was shown to regulate AP-1 trimerization, explaining how O-Nefs lacking this phosphosite counteract tetherin but most M-Nefs do not. These observations show how the higher-order organization of a vesicular coat can be allosterically modulated to direct cargoes to distinct fates.
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