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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/7422788
- author
- Valiaho, Jouni
; Faisal, Imrul
; Ortutay, Csaba
; Smith, C. I. Edvard
and Vihinen, Mauno
LU
- organization
- publishing date
- 2015
- 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 Inc.
- external identifiers
-
- wos:000354623500009
- scopus:84929506736
- pmid:25777788
- 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
- 2016-04-01 09:57:37
- date last changed
- 2022-04-04 00:59:49
@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}},
keywords = {{BTK; Bruton tyrosine kinase; kinase domain; protein structure; mutation; X-linked agammaglobulinemia; XLA}},
language = {{eng}},
number = {{6}},
pages = {{638--647}},
publisher = {{John Wiley & Sons Inc.}},
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}},
doi = {{10.1002/humu.22791}},
volume = {{36}},
year = {{2015}},
}