Abstract
The ESCRT-I protein Tsg101 plays a critical role in viral budding and endocytic sorting. Although Tsg101 is known to recognize monoubiquitin (Ub1), here we show for the first time that it can also bind several diubiquitins (Ub2), with a preference for K63-linked Ub2. The NMR structure of the Tsg101:K63-Ub2 complex showed that while the Ub1-binding site accommodates the distal domain of Ub2, the proximal domain alternatively binds two different sites, the vestigial active site and an N-terminal helix. Mutation of each site resulted in a distinct phenotype with respect to ubiquitin-dependent recruitment. Mutation in the vestigial active site abrogated the interaction between Tsg101 and the HIV-1 protein Gag, while mutation at the N-terminal helix increased the population of Gag-Tsg101 in the cell interior. Given the broad involvement of Tsg101 in diverse cellular functions, this discovery advances our understanding of how the ESCRT protein recognizes binding partners and sorts endocytic cargo.
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