Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Protein Sci. 2023 Sep;32(9):e4750. doi: 10.1002/pro.4750.
Control of eukaryotic cellular function is heavily reliant on the phosphorylation of proteins at specific amino acid residues, such as serine, threonine, tyrosine, and histidine. Protein kinases that are responsible for this process comprise one of the largest families of evolutionarily related proteins. Dysregulation of protein kinase signaling pathways is a frequent cause of a large variety of human diseases including cancer, autoimmune, neurodegenerative, and cardiovascular disorders. In this study, we mapped all pathogenic mutations in 497 human protein kinase domains from the ClinVar database to the reference structure of Aurora kinase A (AURKA) and grouped them by the relevance to the disease type. Our study revealed that the majority of mutation hotspots associated with cancer are situated within the catalytic and activation loops of the kinase domain, whereas non-cancer-related hotspots tend to be located outside of these regions. Additionally, we identified a hotspot at residue R371 of the AURKA structure that has the highest number of exclusively non-cancer-related pathogenic mutations (21) and has not been previously discussed.
真核细胞功能的控制严重依赖于蛋白质在特定氨基酸残基（如丝氨酸、苏氨酸、酪氨酸和组氨酸）处的磷酸化。负责这一过程的蛋白激酶是进化上相关蛋白最大的家族之一。蛋白激酶信号通路的失调是多种人类疾病（包括癌症、自身免疫、神经退行性和心血管疾病）的常见原因。在这项研究中，我们将 ClinVar 数据库中 497 个人类蛋白激酶结构域的所有致病性突变映射到 Aurora 激酶 A（AURKA）的参考结构上，并根据与疾病类型的相关性对它们进行分组。我们的研究表明，与癌症相关的大多数突变热点位于激酶结构域的催化和激活环内，而非癌症相关的热点则倾向于位于这些区域之外。此外，我们还在 AURKA 结构的残基 R371 处鉴定出一个热点，该热点的致病性突变（21 个）绝大多数与癌症无关，且此前尚未被讨论过。
