Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Cell Syst. 2018 Oct 24;7(4):371-383.e4. doi: 10.1016/j.cels.2018.08.008. Epub 2018 Sep 19.
The functional diversity of kinases enables specificity in cellular signal transduction. Yet how more than 500 members of the human kinome specifically receive regulatory inputs and convey information to appropriate substrates-all while using the common signaling output of phosphorylation-remains enigmatic. Here, we perform statistical co-evolution analysis, mutational scanning, and quantitative live-cell assays to reveal a hierarchical organization of the kinase domain that facilitates the orthogonal evolution of regulatory inputs and substrate outputs while maintaining catalytic function. We find that three quasi-independent "sectors"-groups of evolutionarily coupled residues-represent functional units in the kinase domain that encode for catalytic activity, substrate specificity, and regulation. Sector positions impact both disease and pharmacology: the catalytic sector is significantly enriched for somatic cancer mutations, and residues in the regulatory sector interact with allosteric kinase inhibitors. We propose that this functional architecture endows the kinase domain with inherent regulatory plasticity.
激酶的功能多样性使细胞信号转导具有特异性。然而，人类激酶组中超过 500 个成员如何特异性地接收调节输入，并将信息传递给适当的底物——同时使用磷酸化这一常见的信号输出——仍然是个谜。在这里，我们进行了统计共进化分析、突变扫描和定量活细胞测定，揭示了激酶结构域的层次结构组织，促进了调节输入和底物输出的正交进化，同时保持了催化功能。我们发现，三个准独立的“扇区”——一组进化上相互关联的残基——代表了激酶结构域中的功能单元，编码催化活性、底物特异性和调节。扇区位置既影响疾病又影响药理学：催化扇区显著富集了体细胞癌症突变，而调节扇区中的残基与变构激酶抑制剂相互作用。我们提出，这种功能结构赋予了激酶结构域固有的调节可塑性。
