Calpain cleavage prediction using multiple kernel learning

PLoS One. 2011 May 3;6(5):e19035. doi: 10.1371/journal.pone.0019035.

Abstract

Calpain, an intracellular Ca²⁺-dependent cysteine protease, is known to play a role in a wide range of metabolic pathways through limited proteolysis of its substrates. However, only a limited number of these substrates are currently known, with the exact mechanism of substrate recognition and cleavage by calpain still largely unknown. While previous research has successfully applied standard machine-learning algorithms to accurately predict substrate cleavage by other similar types of proteases, their approach does not extend well to calpain, possibly due to its particular mode of proteolytic action and limited amount of experimental data. Through the use of Multiple Kernel Learning, a recent extension to the classic Support Vector Machine framework, we were able to train complex models based on rich, heterogeneous feature sets, leading to significantly improved prediction quality (6% over highest AUC score produced by state-of-the-art methods). In addition to producing a stronger machine-learning model for the prediction of calpain cleavage, we were able to highlight the importance and role of each feature of substrate sequences in defining specificity: primary sequence, secondary structure and solvent accessibility. Most notably, we showed there existed significant specificity differences across calpain sub-types, despite previous assumption to the contrary. Prediction accuracy was further successfully validated using, as an unbiased test set, mutated sequences of calpastatin (endogenous inhibitor of calpain) modified to no longer block calpain's proteolytic action. An online implementation of our prediction tool is available at http://calpain.org.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Area Under Curve
  • Artificial Intelligence
  • Binding Sites
  • Biochemistry / methods
  • Calcium / chemistry
  • Calcium-Binding Proteins / chemistry
  • Calpain / chemistry*
  • Computational Biology / methods
  • Humans
  • Models, Statistical
  • Normal Distribution
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Reproducibility of Results
  • Software

Substances

  • Calcium-Binding Proteins
  • calpastatin
  • Calpain
  • Calcium