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Published October 10, 2008 | Accepted Version + Supplemental Material
Journal Article Open

Multimodal activation of the ubiquitin ligase SCF by Nedd8 conjugation


Conjugation of ubiquitin-like protein Nedd8 to cullins (neddylation) is essential for the function of cullin-RING ubiquitin ligases (CRLs). Here, we show that neddylation stimulates CRL activity by multiple mechanisms. For the initiator ubiquitin, the major effect is to bridge the ~50 A° gap between naked substrate and E2 ~ Ub bound to SCF. The gap between the acceptor lysine of ubiquitinated substrate and E2 ~ Ub is much smaller, and, consequentially, the impact of neddylation on transfer of subsequent ubiquitins by Cdc34 arises primarily from improved E2 recruitment and enhanced amide bond formation in the E2 active site. The combined effects of neddylation greatly enhance the probability that a substrate molecule acquires ≥ 4 ubiquitins in a single encounter with a CRL. The surprisingly diverse effects of Nedd8 conjugation underscore the complexity of CRL regulation and suggest that modification of other ubiquitin ligases with ubiquitin or ubiquitin-like proteins may likewise have major functional consequences.

Additional Information

© 2008 Elsevier B.V. Received 30 June 2008; revised 30 July 2008; accepted 18 August 2008. Published: October 9, 2008. Available online 9 October 2008. We thank V. Chau, T. Gomez, B. Hao, M. Pagano, and B. Schulman for reagents; B. Schulman for communicating unpublished results; Caltech Protein Expression and Caltech Proteome Exploration Facility for technical assistance; G. Kleiger, S. Shan, X. Zhang, and members of the Deshaies lab for suggestions; and E. Emberley, G. Kleiger, E. Lee, N. Peirce, and S. Shan for comments on the manuscript. This work was funded by U.S. National Institute of Health grant GM065997. R.J.D. is an Investigator of the H.H.M.I. R.J.D. is a founder, shareholder, and consultant for Proteolix.

Attached Files

Accepted Version - nihms74823.pdf

Supplemental Material - SAHmc08_supp.pdf


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