Skip to main content
Article thumbnail
Location of Repository

Calpain Cleavage Prediction Using Multiple Kernel Learning

By David A. duVerle, Yasuko Ono, Hiroyuki Sorimachi and Hiroshi Mamitsuka

Abstract

Calpain, an intracellular -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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3086883
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • http://calpain.org. (external link)
  • Suggested articles

    Citations

    1. (2003). A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I.
    2. (1987). A unique specificity of a calcium activated neutral protease indicated in histone hydrolysis.
    3. (2008). Calpain in the CNS: from synaptic function to neurotoxicity.
    4. (2005). Calpain proteases in cell adhesion and motility.
    5. (2000). Calpain-dependent proteolysis of NF2 protein: involvement in schwannomas and meningiomas.
    6. (1994). Calpain: new perspectives in molecular diversity and physiological-pathological involvement.
    7. (2007). Calpains and human disease.
    8. (2006). Calpains and their multiple roles in diabetes mellitus.
    9. (2005). Calpains in muscle wasting.
    10. (2010). Cascleave: towards more accurate prediction of caspase substrate cleavage sites.
    11. (2007). CASVM: web server for SVM-based prediction of caspase substrates cleavage sites.
    12. (2005). Determination of Peptide Substrate Specificity for m-Calpain by a Peptide Library-based Approach.
    13. (2005). Digestive versus regulatory proteases: on calpain action in vivo.
    14. (1998). Functional defects of a musclespecific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A.
    15. (2000). Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.
    16. (2005). GraBCas: a bioinformatics tool for score-based prediction of Caspase-and Granzyme Bcleavage sites in protein sequences.
    17. (1993). In situ capture of mu-calpain activation in platelets.
    18. (2010). Inhibition of calpain but not caspase activity by spectrin fragments. Cellular & Molecular Biology Letters.
    19. (1995). Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A.
    20. (1993). Novel antibodies specific for proteolyzed forms of protein kinase C: production of anti-peptide antibodies available for in situ analysis of intracellular limited proteolysis.
    21. (2004). On the sequential determinants of calpain cleavage.
    22. (1994). Peptide bond specificity of calpain: proteolysis of human myelin basic protein.
    23. (1996). PEST motifs are not required for rapid calpain-mediated proteolysis of c-fos protein.
    24. (1995). PEST sequences do not influence substrate susceptibility to calpain proteolysis.
    25. (2005). Prediction of caspase cleavage sites using Bayesian bio-basis function neural networks.
    26. (2006). Selective Deletion of the NH2-Terminal Variable Region of Cardiac Troponin T in Ischemia Reperfusion by MyofibrilAssociated m-Calpain Cleavage.
    27. (1997). Site-Directed Mutagenesis of a II Spectrin at Codon 1175 Modulates Its m-Calpain Susceptibility.
    28. (1993). Spatial resolution of fodrin proteolysis in postischemic brain.
    29. (1997). Structure and physiological function of calpains.
    30. (2004). Structure, activation, and biology of calpain.
    31. (2003). The calpain system.
    32. (2007). The calpains: modular designs and functional diversity.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.