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Characterization of All Possible Single-Nucleotide Change Caused Amino Acid Substitutions in the Kinase Domain of Bruton Tyrosine Kinase

Valiaho, Jouni; Faisal, Imrul; Ortutay, Csaba; Smith, C. I. Edvard and Vihinen, Mauno LU (2015) In Human Mutation 36(6). p.638-647
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
BTK, Bruton tyrosine kinase, kinase domain, protein structure, mutation, X-linked agammaglobulinemia, XLA
in
Human Mutation
volume
36
issue
6
pages
638 - 647
publisher
John Wiley & Sons
external identifiers
  • wos:000354623500009
  • scopus:84929506736
ISSN
1059-7794
DOI
10.1002/humu.22791
language
English
LU publication?
yes
id
11cc29d9-ac94-44f7-a487-cb2c934ce8a7 (old id 7422788)
date added to LUP
2015-07-03 07:04:33
date last changed
2017-08-27 03:06:35
@article{11cc29d9-ac94-44f7-a487-cb2c934ce8a7,
  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.},
  author       = {Valiaho, Jouni and Faisal, Imrul and Ortutay, Csaba and Smith, C. I. Edvard and Vihinen, Mauno},
  issn         = {1059-7794},
  keyword      = {BTK,Bruton tyrosine kinase,kinase domain,protein structure,mutation,X-linked agammaglobulinemia,XLA},
  language     = {eng},
  number       = {6},
  pages        = {638--647},
  publisher    = {John Wiley & Sons},
  series       = {Human Mutation},
  title        = {Characterization of All Possible Single-Nucleotide Change Caused Amino Acid Substitutions in the Kinase Domain of Bruton Tyrosine Kinase},
  url          = {http://dx.doi.org/10.1002/humu.22791},
  volume       = {36},
  year         = {2015},
}