Unmasking determinants of specificity in the human kinome.
Unmasking determinants of specificity in the human kinome.
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DOI：
10.1016/j.cell.2015.08.057
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发表时间：
2015-09-24
期刊：
影响因子：
64.5
通讯作者：
Linding R
中科院分区：
文献类型：
--
作者：
Creixell P;Palmeri A;Miller CJ;Lou HJ;Santini CC;Nielsen M;Turk BE;Linding R
蛋白激酶通过快速准确的信号处理来控制细胞对环境信号的反应。这种高保真能力的故障是癌症和其他疾病的驱动力。因此，我们对激酶结构域中哪些氨基酸编码底物特异性（所谓的特异性决定簇（DoS））的有限理解构成了癌症信号传导的主要障碍。在这里，我们系统地发现了几个DoS和实验验证其中三个，命名为αC1，αC3和APE-7残基。我们表明，DoS形成稀疏网络的非保守残基跨越遥远的地区。我们的研究结果揭示了残基间变构在特异性和激酶活性和特异性的进化解耦中可能发挥的作用，这些激酶活性和特异性似乎加载在独立的残基组上。最后，我们发现了驱动SH 2结构域特异性的类似特性，并展示了如何利用DoS的识别来阐明对癌症中信号网络作用的更深入理解。在激酶和SH 2结构域中驱动特异性的残基在全球范围内被鉴定出三个新的此类残基，称为αC1，αC3和APE-7，特异性和催化活性似乎是由不同的残基组编码的决定簇的全局识别允许重新布线突变的建模确定驱动激酶和结合磷酸化位点的SH 2结构域的特异性的残基为信号网络突变的系统解释铺平了道路。
Protein kinases control cellular responses to environmental cues by swift and accurate signal processing. Breakdowns in this high-fidelity capability are a driving force in cancer and other diseases. Thus, our limited understanding of which amino acids in the kinase domain encode substrate specificity, the so-called determinants of specificity (DoS), constitutes a major obstacle in cancer signaling. Here, we systematically discover several DoS and experimentally validate three of them, named the αC1, αC3, and APE-7 residues. We demonstrate that DoS form sparse networks of non-conserved residues spanning distant regions. Our results reveal a likely role for inter-residue allostery in specificity and an evolutionary decoupling of kinase activity and specificity, which appear loaded on independent groups of residues. Finally, we uncover similar properties driving SH2 domain specificity and demonstrate how the identification of DoS can be utilized to elucidate a greater understanding of the role of signaling networks in cancer ( [this issue of Cell]). Residues driving specificity in the kinase and SH2 domains are globally identified Three new such residues, termed αC1, αC3, and APE-7, are experimentally validated Specificity and catalytic activity appear to be encoded in distinct sets of residues The global identification of determinants allows the modeling of rewiring mutations Determining the residues that drive the specificity of kinases and of SH2 domains that bind phosphorylation sites paves the way for a systematic interpretation of mutations on signaling networks.