Characterization of All Possible Single-Nucleotide Change Caused Amino Acid Substitutions in the Kinase Domain of Bruton Tyrosine Kinase
Författare
Summary, in English
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.
Avdelning/ar
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- Proteinbioinformatik
Publiceringsår
2015
Språk
Engelska
Sidor
638-647
Publikation/Tidskrift/Serie
Human Mutation
Volym
36
Issue
6
Dokumenttyp
Artikel i tidskrift
Förlag
John Wiley & Sons Inc.
Ämne
- Medical Genetics
Nyckelord
- BTK
- Bruton tyrosine kinase
- kinase domain
- protein structure
- mutation
- X-linked agammaglobulinemia
- XLA
Status
Published
Forskningsgrupp
- Protein Bioinformatics
ISBN/ISSN/Övrigt
- ISSN: 1059-7794