Schmidt Michael W, McQuary Philip R, Wee Susan, Hofmann Kay, Wolf Dieter A
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Mol Cell. 2009 Sep 11;35(5):586-97. doi: 10.1016/j.molcel.2009.07.024.
The COP9 signalosome (CSN) is thought to maintain the stability of cullin-RING ubiquitin ligases (CRL) by limiting the autocatalytic destruction of substrate adapters such as F box proteins (FBPs). CAND1, a protein associated with unneddylated CUL1, was proposed to assist in this role in an as yet unclear fashion. We found that only a subset of Schizosaccharomyces pombe FBPs, which feature a critical F box proline that promotes their interaction with CUL1, required CSN for stability. Unlike the CRL3 adaptor Btb3p, none of the CSN-sensitive FBPs were affected by deletion of ubp12. Contrary to current models, CAND1 does not control adaptor stability but maintains the cellular balance of CRL1 complexes by preventing rare FBPs from being outcompeted for binding to CUL1 by more ample adapters. These findings were integrated into a refined model of CRL control in which substrate availability toggles CRLs between independent CSN and CAND1 cycles.
COP9信号体（CSN）被认为通过限制诸如F盒蛋白（FBP）等底物衔接蛋白的自催化破坏来维持Cullin-RING泛素连接酶（CRL）的稳定性。CAND1是一种与未被NEDD化的CUL1相关的蛋白质，它被认为以一种尚不清楚的方式协助发挥这一作用。我们发现，只有一小部分粟酒裂殖酵母FBP需要CSN来维持稳定性，这些FBP具有促进其与CUL1相互作用的关键F盒脯氨酸。与CRL3衔接蛋白Btb3p不同，CSN敏感的FBP没有一个受到ubp12缺失的影响。与当前模型相反，CAND1并不控制衔接蛋白的稳定性，而是通过防止稀有FBP被更丰富的衔接蛋白竞争结合CUL1来维持CRL1复合物的细胞平衡。这些发现被整合到一个CRL调控的精细模型中，其中底物可用性在独立的CSN和CAND1循环之间切换CRL。
