Mittag Tanja, Orlicky Stephen, Choy Wing-Yiu, Tang Xiaojing, Lin Hong, Sicheri Frank, Kay Lewis E, Tyers Mike, Forman-Kay Julie D
Program in Molecular Structure and Function, Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8.
Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17772-7. doi: 10.1073/pnas.0809222105. Epub 2008 Nov 13.
Intrinsically disordered proteins play critical but often poorly understood roles in mediating protein interactions. The interactions of disordered proteins studied to date typically entail structural stabilization, whether as a global disorder-to-order transition or minimal ordering of short linear motifs. The disordered cyclin-dependent kinase (CDK) inhibitor Sic1 interacts with a single site on its receptor Cdc4 only upon phosphorylation of its multiple dispersed CDK sites. The molecular basis for this multisite-dependent interaction with a single receptor site is not known. By NMR analysis, we show that multiple phosphorylated sites on Sic1 interact with Cdc4 in dynamic equilibrium with only local ordering around each site. Regardless of phosphorylation status, Sic1 exists in an intrinsically disordered state but is surprisingly compact with transient structure. The observation of this unusual binding mode between Sic1 and Cdc4 extends the understanding of protein interactions from predominantly static complexes to include dynamic ensembles of intrinsically disordered states.
内在无序蛋白质在介导蛋白质相互作用中发挥着关键作用，但人们对此往往了解甚少。迄今为止所研究的无序蛋白质相互作用通常需要结构稳定，无论是从全局的无序到有序转变，还是短线性基序的最小程度有序化。无序的细胞周期蛋白依赖性激酶（CDK）抑制剂Sic1只有在其多个分散的CDK位点发生磷酸化后，才会与受体Cdc4上的单个位点相互作用。这种多位点依赖性与单个受体位点相互作用的分子基础尚不清楚。通过核磁共振分析，我们发现Sic1上的多个磷酸化位点与Cdc4相互作用，处于动态平衡，每个位点周围只有局部有序化。无论磷酸化状态如何，Sic1都处于内在无序状态，但令人惊讶的是其结构紧凑且具有瞬态结构。Sic1与Cdc4之间这种不寻常结合模式的发现，将对蛋白质相互作用的理解从主要是静态复合物扩展到包括内在无序状态的动态集合。
