Pathogenic mutation hotspots in protein kinase domain structure

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.

Automated summary

The dysregulation of protein kinase signaling pathways is frequently associated with various human diseases, including cancer. In this study, pathogenic mutations in human protein kinase domains were mapped and categorized based on their relevance to disease type. It was found that cancer-associated mutations primarily occurred within the catalytic and activation loops of the kinase domain, while non-cancer-related mutations were mainly located outside of these regions. Additionally, a previously unexplored hotspot at residue R371 of the AURKA structure was identified, which harbored a high number of exclusively non-cancer-related pathogenic mutations (21).