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Deciphering the Role of PKC in Calpain-CAST System Through Formal Modeling Approach

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Bioinformatics and Biomedical Engineering (IWBBIO 2019)

Part of the book series: Lecture Notes in Computer Science ((LNBI,volume 11465))

Abstract

Calcium-activated calpain has critical role in a variety of calcium regulated processes. Calcium activates two other proteins, Calpastatin (CAST) and Protein Kinase C (PKC) to make a regulatory network which is pivotal in cell physiology. CAST binds with calpain to form complex for hampering its hyperactivation. PKC phosphorylates CAST while calpain proteolyzes active PKC and increases calcium influx. Based on biological knowledge, a qualitative (discrete) model is constructed that provides new insights into the dynamics of calpain-CAST and PKC relationship. The model predicts that PKC maintains calpain-CAST complex by interacting with both active calpain and CAST. It is also observed that in physiological condition, there is a homeostatic behavior between calcium, CAST and PKC. Some significant discrete cycles are also identified by analyzing betweenness centralities of the discrete states. There is one stable state in the model in which calpain and calcium are hyperactivated while CAST and PKC are inactivated. The model is validated through the stochastic Petri Net model that further reveals its quantitative dynamical behaviors. Physiology is perturbed by hyperactivation of calpain which results in the deregulation of homeostasis. Both models suggest that inhibition of calpain by CAST is a better therapeutic strategy which requires healthy assistance from PKC. In conclusion, homeostasis of calcium, CAST and PKC is pivotal for a healthy state.

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Authors and Affiliations

  1. Research Center for Modeling and Simulation, National University of Sciences and Technology, Islamabad, Pakistan

    Javaria Ashraf

  2. Department of Computer Science and Information Technology, University of Malakand, Chakdara, Pakistan

    Jamil Ahmad

  3. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical Sciences, University of Karachi, Karachi, Pakistan

    Zaheer Ul-Haq

Authors
  1. Javaria Ashraf
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  2. Jamil Ahmad
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  3. Zaheer Ul-Haq
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Corresponding author

Correspondence to Jamil Ahmad .

Editor information

Editors and Affiliations

  1. Department of Computer Architecture and Computer Technology Higher Technical School of Information Technology and Telecommunications Engineering, CITIC-UGR, Granada, Spain

    Ignacio Rojas

  2. ETSIIT, University of Granada, Granada, Spain

    Olga Valenzuela

  3. CITIC-UGR, University of Granada, Granada, Spain

    Fernando Rojas

  4. Fundacion Progreso y Salud, Granada, Spain

    Francisco Ortuño

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Ashraf, J., Ahmad, J., Ul-Haq, Z. (2019). Deciphering the Role of PKC in Calpain-CAST System Through Formal Modeling Approach. In: Rojas, I., Valenzuela, O., Rojas, F., Ortuño, F. (eds) Bioinformatics and Biomedical Engineering. IWBBIO 2019. Lecture Notes in Computer Science(), vol 11465. Springer, Cham. https://doi.org/10.1007/978-3-030-17938-0_6

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  • DOI: https://doi.org/10.1007/978-3-030-17938-0_6

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-17937-3

  • Online ISBN: 978-3-030-17938-0

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