Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernandez Almagro 3, E28029 Madrid, Spain.
BMC Bioinformatics. 2011;12 Suppl 4(Suppl 4):S1. doi: 10.1186/1471-2105-12-S4-S1. Epub 2011 Jul 5.
Protein Kinases are a superfamily of proteins involved in crucial cellular processes such as cell cycle regulation and signal transduction. Accordingly, they play an important role in cancer biology. To contribute to the study of the relation between kinases and disease we compared pathogenic mutations to neutral mutations as an extension to our previous analysis of cancer somatic mutations. First, we analyzed native and mutant proteins in terms of amino acid composition. Secondly, mutations were characterized according to their potential structural effects and finally, we assessed the location of the different classes of polymorphisms with respect to kinase-relevant positions in terms of subfamily specificity, conservation, accessibility and functional sites.
Pathogenic Protein Kinase mutations perturb essential aspects of protein function, including disruption of substrate binding and/or effector recognition at family-specific positions. Interestingly these mutations in Protein Kinases display a tendency to avoid structurally relevant positions, what represents a significant difference with respect to the average distribution of pathogenic mutations in other protein families.
Disease-associated mutations display sound differences with respect to neutral mutations: several amino acids are specific of each mutation type, different structural properties characterize each class and the distribution of pathogenic mutations within the consensus structure of the Protein Kinase domain is substantially different to that for non-pathogenic mutations. This preferential distribution confirms previous observations about the functional and structural distribution of the controversial cancer driver and passenger somatic mutations and their use as a proxy for the study of the involvement of somatic mutations in cancer development.
蛋白激酶是一类参与细胞周期调控和信号转导等关键细胞过程的蛋白质超家族，因此在癌症生物学中发挥着重要作用。为了研究激酶与疾病之间的关系，我们将致病突变与中性突变进行了比较，这是对我们之前癌症体细胞突变分析的扩展。首先，我们根据氨基酸组成分析了天然蛋白和突变蛋白。其次，根据潜在的结构效应对突变进行了特征描述，最后，我们根据亚家族特异性、保守性、可及性和功能位点评估了不同类别多态性相对于激酶相关位置的位置。
致病蛋白激酶突变扰乱了蛋白功能的基本方面，包括破坏了家族特异性位置的底物结合和/或效应物识别。有趣的是，这些蛋白激酶中的突变倾向于避免结构相关位置，这与其他蛋白家族中致病突变的平均分布有显著差异。
与中性突变相比，与疾病相关的突变具有明显的差异：每种突变类型都有特定的几个氨基酸，不同的结构特性表征每个类别，并且致病突变在蛋白激酶结构域的共识结构内的分布与非致病突变有很大不同。这种优先分布证实了先前关于有争议的癌症驱动和乘客体细胞突变的功能和结构分布的观察结果，以及它们作为研究体细胞突变在癌症发展中的作用的替代物的使用。
