Imperial College London
Alternate

ProfessorMichaelSternberg

Faculty of Natural Sciences, Department of Life Sciences

Director, Systems Biology and Bioinformatics Centre
 
 
 
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Contact

 

+44 (0)20 7594 5212m.sternberg Website

 
 
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Location

 

306Sir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{David:2015:10.1016/j.jmb.2015.07.004,
author = {David, A and Sternberg, MJ},
doi = {10.1016/j.jmb.2015.07.004},
journal = {Journal of Molecular Biology},
pages = {2886--2898},
title = {The contribution of missense mutations in core and rim residues of protein-protein interfaces to human disease.},
url = {http://dx.doi.org/10.1016/j.jmb.2015.07.004},
volume = {427},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Missense mutations at protein-protein interaction (PPIs) sites, called interfaces, are important contributors to human disease. Interfaces are non-uniform surface areas characterized by two main regions, 'core' and 'rim', which differ in terms of evolutionary conservation and physico-chemical properties. Moreover, within interfaces, only a small subset of residues ('hot spots') is crucial for the binding free energy of the protein-protein complex. We performed a large-scale structural analysis of human single amino acid variations (SAVs) and demonstrated that disease-causing mutations are preferentially located within the interface core, as opposed to the rim (p< 0.01). In contrast, the interface rim is significantly enriched in polymorphisms, similar to the remaining non-interacting surface. Energetic hot spots tend to be enriched in disease-causing mutations compared to non-hot spots (p=0.05), regardless of their occurrence in core or rim residues. For individual amino acids, the frequency of substitution into a polymorphism or disease-causing mutation differed to other amino acids and was related to its structural location, as was the type of physico-chemical change introduced by the SAV. In conclusion, this study demonstrated the different distribution and properties of disease-causing SAVs and polymorphisms within different structural regions and in relation to the energetic contribution of amino acid in protein-protein interfaces, thus highlighting the importance of a structural system biology approach for predicting the effect of SAVs.
AU  - David,A
AU  - Sternberg,MJ
DO  - 10.1016/j.jmb.2015.07.004
EP  - 2898
PY  - 2015///
SN  - 1089-8638
SP  - 2886
TI  - The contribution of missense mutations in core and rim residues of protein-protein interfaces to human disease.
T2  - Journal of Molecular Biology
UR  - http://dx.doi.org/10.1016/j.jmb.2015.07.004
UR  - http://hdl.handle.net/10044/1/25182
VL  - 427
ER  -
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