Cyclin B and cyclin A confer different substrate recognition properties on CDK2
Cyclin B and cyclin A confer different substrate recognition properties on CDK2
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DOI：
10.4161/cc.6.11.4278
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发表时间：
2007-06-01
期刊：
影响因子：
4.3
通讯作者：
Johnson, Louise N.
中科院分区：
文献类型：
--
作者：
Brown, Nick R.;Lowe, Ed D.;Johnson, Louise N.
细胞周期的转变由细胞周期蛋白依赖性蛋白激酶（CDK）调节。细胞周期蛋白激活各自的 CDK 并赋予底物识别特性。我们报告了磷酸化 CDK2/细胞周期蛋白 B 的结构，并表明细胞周期蛋白 B 赋予 CDK2（通常与 S 期相关的激酶）类似 M 期的特性。细胞周期蛋白 B 产生与细胞周期蛋白 A 产生的 CDK2 几乎相同的激活构象。细胞周期蛋白 A 和细胞周期蛋白 B 在募集位点上存在差异，在细胞周期蛋白 A 中，募集位点用于募集含有 RXL 基序的底物。由于序列差异，细胞周期蛋白 B 中的该位点比细胞周期蛋白 A 中的 RXL 基序结合更弱。尽管激酶结构相似，但磷酸化 CDK2/细胞周期蛋白 B 磷酸化底物，例如核纤层蛋白和源自 p107 的模型肽，其序列 SPXX 不同于典型的 CDK2/细胞周期蛋白 A 底物识别基序 SPXK。这些非规范位点的 CDK2/细胞周期蛋白 B 磷酸化不依赖于 RXL 募集基序的存在。 p107 肽包含两个 SP 基序，每个基序后跟一个非规范序列，其中只有一个位点 (Ser640) 被 pCDK2/细胞周期蛋白 A 磷酸化，而两个位点被 pCDK2/细胞周期蛋白 B 磷酸化。第二个位点距离 RXL 基序太近，无法使细胞周期蛋白 A 募集位点发挥作用，因为之前的工作表明催化位点丝氨酸和 RXL 基序之间必须至少有 16 个残基。因此，细胞周期蛋白 A 和 B 除了促进 CDK2 中激活构象转换的作用外，还提供不同的底物特异性。
The transitions of the cell cycle are regulated by the cyclin dependent protein kinases (CDKs). The cyclins activate their respective CDKs and confer substrate recognition properties. We report the structure of phospho-CDK2/cyclin B and show that cyclin B confers M phase-like properties on CDK2, the kinase that is usually associated with S phase. Cyclin B produces an almost identical activated conformation of CDK2 as that produced by cyclin A. There are differences between cyclin A and cyclin B at the recruitment site, which in cyclin A is used to recruit substrates containing an RXL motif. Because of sequence differences this site in cyclin B binds RXL motifs more weakly than in cyclin A. Despite similarity in kinase structures, phospho-CDK2/cyclin B phosphorylates substrates, such as nuclear lamin and a model peptide derived from p107, at sequences SPXX that differ from the canonical CDK2/cyclin A substrate recognition motif, SPXK. CDK2/cyclin B phosphorylation at these non-canonical sites is not dependent on the presence of a RXL recruitment motif. The p107 peptide contains two SP motifs each followed by a non canonical sequence of which only one site (Ser640) is phosphorylated by pCDK2/cyclin A while two sites are phosphorylated by pCDK2/cyclin B. The second site is too close to the RXL motif to allow the cyclin A recruitment site to be effective, as previous work has shown that there must be at least 16 residues between the catalytic site serine and the RXL motif. Thus the cyclins A and B in addition to their role in promoting the activatory conformational switch in CDK2, also provide differential substrate specificity.