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Autoinhibition mechanism of the ubiquitin-conjugating enzyme UBE2S by autoubiquitination.

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Dybkov,  O.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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Urlaub,  H.
Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society;

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Citation

Liess, A. K. L., Kucerova, A., Schweimer, K., Yu, L., Roumeliotis, T. I., Diebold, M., et al. (2019). Autoinhibition mechanism of the ubiquitin-conjugating enzyme UBE2S by autoubiquitination. Structure, 27(8), 1195-1210. doi:10.1016/j.str.2019.05.008.


Cite as: http://hdl.handle.net/21.11116/0000-0003-DDF7-E
Abstract
Ubiquitin-conjugating enzymes (E2s) govern key aspects of ubiquitin signaling. Emerging evidence suggests that the activities of E2s are modulated by posttranslational modifications; the structural underpinnings, however, are largely unclear. Here, we unravel the structural basis and mechanistic consequences of a conserved autoubiquitination event near the catalytic center of E2s, using the human anaphase-promoting complex/cyclosome-associated UBE2S as a model system. Crystal structures we determined of the catalytic ubiquitin carrier protein domain combined with MD simulations reveal that the active-site region is malleable, which permits an adjacent ubiquitin acceptor site, Lys+5, to be ubiquitinated intramolecularly. We demonstrate by NMR that the Lys+5-linked ubiquitin inhibits UBE2S by obstructing its reloading with ubiquitin. By immunoprecipitation, quantitative mass spectrometry, and siRNA-and-rescue experiments we show that Lys+5 ubiquitination of UBE2S decreases during mitotic exit but does not influence proteasomal turnover of this E2. These findings suggest that UBE2S activity underlies inherent regulation during the cell cycle.