MBE Advance Access published online on January 30, 2007
Molecular Biology and Evolution, doi:10.1093/molbev/msm022
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Research Article |
Functional Coevolutionary Networks of the Hsp70-Hop-Hsp90 System Revealed through Computational Analyses
1 Evolutionary Genetics and Bioinformatics Laboratory, Department of Genetics, Smurfit Institute of Genetics, University of Dublin, Trinity College
2 Molecular Evolution and Bioinformatics Laboratory, Department of Biology, National University of Ireland, Maynooth, Ireland
* Corresponding Author: Dr. Mario A. Fares, Telephone: 353 1 8963521, Email: faresm{at}tcd.ie
Accepted for publication January 26, 2007.
Currently, the identification of groups of amino acid residues that are important in the function, structure or interaction of a protein can be both costly and prohibitively complex, involving vast numbers of mutagenesis experiments. Here, we present the application of a novel computational method, which identifies the presence of coevolution in a dataset, thereby enabling the a priori identification of amino acid residues that play an important role in protein function. We have applied this method to the heat shock protein (Hsp) protein folding system, studying the network between Hsp70, Hsp90 and Hop. Our analysis has identified functional residues within the TPR1 and TPR2a domains in Hop, previously shown to be interacting with Hsp70 and Hsp90 respectively. Further, we have identified significant residues elsewhere in Hop within domains that have been recently proposed as being important for Hop interaction with both Hsp70 and/or Hsp90. In addition, several amino acid sites present in groups of coevolution were identified as three-dimensionally or linearly proximal to functionally important sites or domains. Based on our results, we also investigate a further functional domain within Hop, between TPR1 and TPR2a, which we suggest as being functionally important in the interaction of Hop with both Hsp70 and Hsp90 whether directly or otherwise. Our method has identified all of the previously characterized functionally important regions in this system, thereby indicating the power of this method in the a priori identification of important regions for site-directed mutagenesis studies.
Key Words: Hsp90 • Hop • Hsp70 • Functional Coevolution
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