Journal
MOLECULAR CELL
Volume 62, Issue 6, Pages 918-928Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.04.031
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Funding
- Deutsche Forschungsgemeinschaft (Priority Program 1365) [SFB 740]
- Deutsch-Israelische Projektkooperation (DIP)
- LOEWE program
- Ubiquitin Networks
- Cluster of Excellence Frankfurt (Macromolecular Complexes)
- Lichtenberg professorship of the Volkswagen Foundation
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Ubiquitin conjugation is an essential process modulating protein function in eukaryotic cells. Surprisingly, little is known about how the progressive assembly of ubiquitin chains is managed by the responsible enzymes. Only recently has ubiquitin binding activity emerged as an important factor in chain formation. The Ubc7 activator Cue1 carries a ubiquitin binding CUE domain that substantially stimulates K48-linked polyubiquitination mediated by Ubc7. Our results from NMR-based analysis and in vitro ubiquitination reactions point out that two parameters accelerate ubiquitin chain assembly: the increasing number of CUE binding sites and the position of CUE binding within a growing chain. In particular, interactions with a ubiquitin moiety adjacent to the acceptor ubiquitin facilitate chain elongation. These data indicate a mechanism for ubiquitin binding in which Cue1 positions Ubc7 and the distal acceptor ubiquitin for rapid polyubiquitination. Disrupting this mechanism results in dysfunction of the ERAD pathway by a delayed turnover of substrates.
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