Sheng Jun, Kumagai Akiko, Dunphy William G, Varshavsky Alexander
Division of Biology, 147-75, California Institute of Technology, 1200 East California Blvd, Pasadena, CA 91125, USA.
EMBO J. 2002 Nov 15;21(22):6061-71. doi: 10.1093/emboj/cdf626.
c-MOS, a MAP kinase kinase kinase, is a regulator of oocyte maturation. The concentration of c-MOS is controlled in part through its conditional degradation. Previous studies proposed the "second-codon rule", according to which the N-terminal proline (Pro) of c-MOS is a destabilizing residue that targets c-MOS for degradation. We analyzed the degradation signal (degron) of c-MOS in Xenopus oocytes, found it to be a portable degron, and demonstrated that, contrary to the model above, the N-terminal Pro residue of c-MOS is entirely dispensable for its degradation if Ser-2 (encoded Ser-3) of c-MOS is replaced by a small non-phosphorylatable residue such as Gly. The dependence of c-MOS degradation on N-terminal Pro is shown to be caused by a Pro-mediated downregulation of the net phosphorylation of Ser-2, a modification that halts c-MOS degradation in oocytes. Thus, the N-terminal Pro residue of c-MOS is not a recognition determinant for a ubiquitin ligase, in agreement with earlier evidence that Pro is a stabilizing residue in the N-end rule.
c-MOS是一种丝裂原活化蛋白激酶激酶激酶，是卵母细胞成熟的调节因子。c-MOS的浓度部分通过其条件性降解来控制。先前的研究提出了“第二个密码子规则”，根据该规则，c-MOS的N端脯氨酸（Pro）是一个不稳定残基，可将c-MOS靶向降解。我们分析了非洲爪蟾卵母细胞中c-MOS的降解信号（降解结构域），发现它是一个可转移的降解结构域，并证明，与上述模型相反，如果c-MOS的Ser-2（编码Ser-3）被一个小的不可磷酸化残基（如Gly）取代，c-MOS的N端Pro残基对于其降解完全是可有可无的。c-MOS降解对N端Pro的依赖性被证明是由Pro介导的Ser-2净磷酸化的下调引起的，这种修饰会阻止卵母细胞中c-MOS的降解。因此，c-MOS的N端Pro残基不是泛素连接酶的识别决定因素，这与早期证据一致，即Pro是N端规则中的一个稳定残基。
