Parker D, Jhala U S, Radhakrishnan I, Yaffe M B, Reyes C, Shulman A I, Cantley L C, Wright P E, Montminy M
Joslin Diabetes Center, Research Division, Boston, Massachusetts, USA.
Mol Cell. 1998 Sep;2(3):353-9. doi: 10.1016/s1097-2765(00)80279-8.
Ser-133 phosphorylation of CREB within the kinase-inducible domain (KID) promotes target gene activation via complex formation with the KIX domain of the coactivator CBP. Concurrent phosphorylation of CREB at Ser-142 inhibits transcriptional induction via an unknown mechanism. Unstructured in the free state, KID folds into a helical structure upon binding to KIX. Using site-directed mutagenesis based on the NMR structure of the KID:KIX complex, we have examined the mechanisms by which Ser-133 and Ser-142 phosphorylation regulate CREB activity. Our results indicate that phospho-Ser-133 stablizes whereas phospho-Ser-142 disrupts secondary structure-mediated interactions between CREB and CBP. Thus, differential phosphorylation of CREB may form the basis by which upstream signals regulate the specificity of target gene activation.
激酶诱导结构域（KID）内的CREB第133位丝氨酸磷酸化通过与共激活因子CBP的KIX结构域形成复合物来促进靶基因激活。CREB第142位丝氨酸的同时磷酸化通过未知机制抑制转录诱导。KID在游离状态下无结构，与KIX结合后折叠成螺旋结构。基于KID:KIX复合物的核磁共振结构进行定点诱变，我们研究了第133位和第142位丝氨酸磷酸化调节CREB活性的机制。我们的结果表明，磷酸化的丝氨酸133起稳定作用，而磷酸化的丝氨酸142破坏了CREB与CBP之间二级结构介导的相互作用。因此，CREB的差异磷酸化可能构成上游信号调节靶基因激活特异性的基础。
