Conservation and covariance in PH domain sequences: physicochemical profile and information theoretical analysis of XLA-causing mutations in the Btk PH domain.
Author
Summary, in English
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.
Publishing year
2004
Language
English
Pages
267-276
Publication/Series
Protein Engineering Design & Selection
Volume
17
Issue
3
Links
Document type
Journal article
Publisher
Oxford University Press
Topic
- Medical Genetics
Keywords
- Tertiary: genetics
- Protein Structure
- Physical: methods
- Chemistry
- Agammaglobulinemia: etiology
- Agammaglobulinemia: genetics
- Protein-Tyrosine Kinases: chemistry
- Protein-Tyrosine Kinases: genetics
- Solvents: chemistry
Status
Published
ISBN/ISSN/Other
- ISSN: 1741-0126