Autoinhibitory regulation of SCF-mediated ubiquitination by human cullin 1's C-terminal tail.

Proceedings of the National Academy of Sciences of the United States of America
Kosj YamoahZhen-Qiang Pan

Abstract

SCF (Skp1 x CUL1 x F-box protein x ROC1) E3 ubiquitin ligase and Cdc34 E2-conjugating enzyme catalyze polyubiquitination in a precisely regulated fashion. Here, we describe biochemical evidence suggesting an autoinhibitory role played by the human CUL1 ECTD (extreme C-terminal domain; spanning the C-terminal 50 amino acids), a region that is predicted to contact the ROC1 RING finger protein by structural studies. We showed that ECTD did not contribute to CUL1's stable association with ROC1. Remarkably, deletion of ECTD, or missense mutations designed to disrupt the predicted ECTD x ROC1 interaction, markedly increased the ability of SCF(betaTrCP2) to promote IkappaB alpha polyubiquitination and polyubiquitin chain assembly by Cdc34 in vitro. Thus, disruption of ECTD yields in vitro effects that parallel SCF activation by Nedd8 conjugation to CUL1. We propose that SCF may be subject to autoinhibitory regulation, in which Nedd8 conjugation acts as a molecular switch to drive the E3 into an active state by diminishing the inhibitory ECTD x ROC1 interaction.

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Citations

Jun 19, 2013·Nature Communications·Donald E SprattGary S Shaw
Apr 9, 2009·Nature Reviews. Molecular Cell Biology·Brenda A Schulman, J Wade Harper
Jul 19, 2011·Nature Structural & Molecular Biology·Matthew F CalabreseBrenda A Schulman
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Jul 21, 2009·Proceedings of the National Academy of Sciences of the United States of America·Nathalie Meyer-SchallerMatthias Peter
Jan 16, 2013·Proceedings of the National Academy of Sciences of the United States of America·Dmitry LyumkisClaudio A P Joazeiro
Aug 5, 2011·The Journal of Biological Chemistry·Kenneth WuZhen-Qiang Pan
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