Advanced

Conservation and covariance in PH domain sequences: physicochemical profile and information theoretical analysis of XLA-causing mutations in the Btk PH domain.

Shen, Bairong and Vihinen, Mauno LU (2004) In Protein Engineering Design & Selection 17(3). p.267-276
Abstract
Mutations that cause X-linked agammaglobulinemia (XLA) appear throughout the Bruton tyrosine kinase (Btk) sequence, including the pleckstrin homology (PH) domain. To analyze the basis of this disease with respect to protein structure, we studied the relationships between PH domain sequences and structures by comparing sequence-based profiles of physicochemical properties and solvent accessibility profiles. The diversity of the distribution of amino acids was measured by calculating entropies for sequences containing mutations at different positions in multiple sequence alignments. Mutual information was calculated to quantify positional covariation. Eight conserved extrema were apparent in all profiles. The majority of the XLA... (More)
Mutations that cause X-linked agammaglobulinemia (XLA) appear throughout the Bruton tyrosine kinase (Btk) sequence, including the pleckstrin homology (PH) domain. To analyze the basis of this disease with respect to protein structure, we studied the relationships between PH domain sequences and structures by comparing sequence-based profiles of physicochemical properties and solvent accessibility profiles. The diversity of the distribution of amino acids was measured by calculating entropies for sequences containing mutations at different positions in multiple sequence alignments. Mutual information was calculated to quantify positional covariation. Eight conserved extrema were apparent in all profiles. The majority of the XLA disease-causing mutations in the Btk PH domain were found at positions having significant mutual information, indicating that there are covariant constraints for both structure and function. Together with additional structural analyses, all the XLA mutations that were analyzed could be explained at the molecular level. The method developed here is applicable to the design of mutations for protein engineering. (Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Tertiary: genetics, Protein Structure, Physical: methods, Chemistry, Agammaglobulinemia: etiology, Agammaglobulinemia: genetics, Protein-Tyrosine Kinases: chemistry, Protein-Tyrosine Kinases: genetics, Solvents: chemistry
in
Protein Engineering Design & Selection
volume
17
issue
3
pages
267 - 276
publisher
Oxford University Press
external identifiers
  • PMID:15082835
  • Scopus:2942689385
ISSN
1741-0126
DOI
10.1093/protein/gzh030
language
English
LU publication?
no
id
60628cbf-275a-429a-bee1-46df4162cea5 (old id 3635478)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/15082835?dopt=Abstract
date added to LUP
2013-06-12 16:11:51
date last changed
2016-10-13 04:27:47
@misc{60628cbf-275a-429a-bee1-46df4162cea5,
  abstract     = {Mutations that cause X-linked agammaglobulinemia (XLA) appear throughout the Bruton tyrosine kinase (Btk) sequence, including the pleckstrin homology (PH) domain. To analyze the basis of this disease with respect to protein structure, we studied the relationships between PH domain sequences and structures by comparing sequence-based profiles of physicochemical properties and solvent accessibility profiles. The diversity of the distribution of amino acids was measured by calculating entropies for sequences containing mutations at different positions in multiple sequence alignments. Mutual information was calculated to quantify positional covariation. Eight conserved extrema were apparent in all profiles. The majority of the XLA disease-causing mutations in the Btk PH domain were found at positions having significant mutual information, indicating that there are covariant constraints for both structure and function. Together with additional structural analyses, all the XLA mutations that were analyzed could be explained at the molecular level. The method developed here is applicable to the design of mutations for protein engineering.},
  author       = {Shen, Bairong and Vihinen, Mauno},
  issn         = {1741-0126},
  keyword      = {Tertiary: genetics,Protein Structure,Physical: methods,Chemistry,Agammaglobulinemia: etiology,Agammaglobulinemia: genetics,Protein-Tyrosine Kinases: chemistry,Protein-Tyrosine Kinases: genetics,Solvents: chemistry},
  language     = {eng},
  number       = {3},
  pages        = {267--276},
  publisher    = {ARRAY(0x94fbbe0)},
  series       = {Protein Engineering Design & Selection},
  title        = {Conservation and covariance in PH domain sequences: physicochemical profile and information theoretical analysis of XLA-causing mutations in the Btk PH domain.},
  url          = {http://dx.doi.org/10.1093/protein/gzh030},
  volume       = {17},
  year         = {2004},
}