Pathogenic mutation hotspots in protein kinase domain structure.

Autor: Medvedev KE; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Schaeffer RD; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Pei J; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Grishin NV; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Jazyk: angličtina
Zdroj: Protein science : a publication of the Protein Society [Protein Sci] 2023 Sep; Vol. 32 (9), pp. e4750.
DOI: 10.1002/pro.4750
Abstrakt: 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.
(© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)
Databáze: MEDLINE
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