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An optimized energy potential can predict SH2 domain-peptide interactions
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- Harvard University
- MIT
- Document Type:
- Manuscript
- Date:
- Received 12 May 2008 20:23 UTC; Posted 12 May 2008
- Subjects:
- Molecular Cell Biology, Bioinformatics
- Abstract:
Peptide recognition modules (PRMs) are used throughout biology to mediate protein-protein interactions, and many PRMs are members of large protein domain families. Members of these families are often quite similar to each other, but each domain recognizes a distinct set of peptides, raising the question of how peptide recognition specificity is achieved using similar protein domains. The analysis of individual protein complex structures often gives answers that are not easily applicable to other members of the same PRM family. Bioinformatics-based approaches, one the other hand, may be difficult to interpret physically. Here we integrate structural information with a large, quantitative data set of SH2-peptide interactions to study the physical origin of domain-peptide specificity. We develop an energy model, inspired by protein folding, based on interactions between the amino acid positions in the domain and peptide. We use this model to successfully predict which SH2 domains and peptides interact and uncover the positions in each that are important for specificity. The energy model is general enough that it can be applied to other members of the SH2 family or to new peptides, and the cross-validation results suggest that these energy calculations will be useful for predicting binding interactions. It can also be adapted to study other PRM families, predict optimal peptides for a given SH2 domain, or study other biological interactions, e.g. protein-DNA interactions.
Discussion
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6 votes
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- License:
- This document is licensed to the public under the Creative Commons Attribution 3.0 License
- How to cite this document:
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Wunderlich, Zeba and Mirny, Leonid. An optimized energy potential can predict SH2 domain-peptide interactions. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2008.1881.1> (2008)
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Pedro Beltrao on 13 May 2008 21:58 UTC
The authors have used available phospho-peptide binding information to SH2 domains to create a model that tries to describe the binding specificity of any SH2 domain. The work is interesting and the potential use of such general models is immense since they could be used to predict the impact of genomic variability.
I find particularly interesting that there is little correlation between the sequence identity of the nearest sequence neighbor of the test domain and the performance of the model. In a similar previous study of SH3 domains (PMID: 16870929) this was one clear limitations found in the study. Possibly the much larger number of SH2 domains with available binding information might be sufficient to cover the binding space of the family.
The low number of experimentally tested peptides however make me doubt that the this model can in fact capture most of binding specificity of the whole SH2 family. The authors could have used different tests to assay the power of the model. For example predicting known SH2 target proteins or the binding of the x-ray ligands for solved SH2 domain complexes.