Accurate Prediction of DnaK-Peptide Binding via Homology Modelling and Experimental Data

Joost Van Durme, Sebastian Maurer-Stroh, Rodrigo Gallardo, Hannah Wilkinson, Frederic Rousseau and Joost Schymkowitz

PLOS Computational Biology, 2009, vol. 5, issue 8, 1-9

Abstract: Molecular chaperones are essential elements of the protein quality control machinery that governs translocation and folding of nascent polypeptides, refolding and degradation of misfolded proteins, and activation of a wide range of client proteins. The prokaryotic heat-shock protein DnaK is the E. coli representative of the ubiquitous Hsp70 family, which specializes in the binding of exposed hydrophobic regions in unfolded polypeptides. Accurate prediction of DnaK binding sites in E. coli proteins is an essential prerequisite to understand the precise function of this chaperone and the properties of its substrate proteins. In order to map DnaK binding sites in protein sequences, we have developed an algorithm that combines sequence information from peptide binding experiments and structural parameters from homology modelling. We show that this combination significantly outperforms either single approach. The final predictor had a Matthews correlation coefficient (MCC) of 0.819 when assessed over the 144 tested peptide sequences to detect true positives and true negatives. To test the robustness of the learning set, we have conducted a simulated cross-validation, where we omit sequences from the learning sets and calculate the rate of repredicting them. This resulted in a surprisingly good MCC of 0.703. The algorithm was also able to perform equally well on a blind test set of binders and non-binders, of which there was no prior knowledge in the learning sets. The algorithm is freely available at http://limbo.vib.be.Author Summary: Molecular chaperones are essential elements of the protein quality control machinery that governs translocation and folding of nascent polypeptides, refolding and degradation of misfolded proteins, and activation of a wide range of client proteins. This variety of functions results from the existence of multiple chaperones with different structures. Chaperones bind to exposed regions of proteins to fulfil their function. The chaperone must hereby recognise a certain signal sequence on the substrate protein. The nature of the sequence that is exposed will determine the types of chaperones that can interact with it, and in the end will also determine the fate of the substrate protein: refolding, translocation, degradation or activation. Knowledge of the binding sequence determinants of molecular chaperones will shed more light on the mechanism of how each chaperone contributes to the cellular protein quality control system.

Date: 2009
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Citations: View citations in EconPapers (3)

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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1000475

DOI: 10.1371/journal.pcbi.1000475

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