Characterization of all possible single-nucleotide change caused amino acid substitutions in the kinase domain of Bruton tyrosine kinase

Human Mutation
J VäliahoM Vihinen

Abstract

Knowledge about features distinguishing deleterious and neutral variations is crucial for interpretation of novel variants. Bruton tyrosine kinase (BTK) contains the highest number of unique disease-causing variations among the human protein kinases, still it is just 10% of all the possible single-nucleotide substitution-caused amino acid variations (SNAVs). In the BTK kinase domain (BTK-KD) can appear altogether 1,495 SNAVs. We investigated them all with bioinformatic and protein structure analysis methods. Most disease-causing variations affect conserved and buried residues disturbing protein stability. Minority of exposed residues is conserved, but strongly tied to pathogenicity. Sixty-seven percent of variations are predicted to be harmful. In 39% of the residues, all the variants are likely harmful, whereas in 10% of sites, all the substitutions are tolerated. Results indicate the importance of the entire kinase domain, involvement in numerous interactions, and intricate functional regulation by conformational change. These results can be extended to other protein kinases and organisms.

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Citations

Feb 18, 2016·BioMed Research International·Zhi JiangGuang Hu
Sep 4, 2015·Human Mutation·Abhishek Niroula, Mauno Vihinen
Aug 19, 2015·BMC Medical Genomics·Abhishek Niroula, Mauno Vihinen
Mar 19, 2016·Human Mutation·Abhishek Niroula, Mauno Vihinen
Feb 23, 2017·Human Mutation·Abhishek Niroula, Mauno Vihinen
Mar 22, 2018·International Journal of Molecular Sciences·Songzhen HeFangyin Dai
Dec 1, 2017·BMC Bioinformatics·Jelena Čalyševa, Mauno Vihinen
May 26, 2020·Proteins·Tyler A MartinAron W Fenton
Mar 20, 2016·Journal of Clinical Immunology·Mingyan FangLennart Hammarström
Feb 6, 2020·Database : the Journal of Biological Databases and Curation·Anasua SarkarMauno Vihinen
Oct 8, 2015·Human Mutation·Miguel VazquezJose M G Izarzugaza
Nov 24, 2020·Journal of Clinical Immunology·Arun Kumar ArunachalamEunice Sindhuvi Edison
Nov 10, 2020·Biochimie·Mauno Vihinen
Aug 6, 2021·Frontiers in Immunology·Rula Zain, Mauno Vihinen

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