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Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII

Corina E Antal1, Julia A Callender1, Alexandr P Kornev2

  • 1Department of Pharmacology, University of California at San Diego, La Jolla, CA 92037, USA; Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92037, USA.

Cell Reports
|August 18, 2015
PubMed

Insights

Understanding protein kinase C (PKC) autoinhibition is key for treating cancer and neurodegenerative diseases. New structural insights reveal how the C2 domain locks PKC in an inactive state, offering therapeutic targets.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Pharmacology

Background:

  • Protein Kinase C (PKC) signaling is crucial for cellular functions, and its dysregulation is implicated in various diseases.
  • Targeting PKC activity is a promising therapeutic strategy for conditions like cancer and neurodegenerative disorders.
  • Understanding the structural basis of PKC autoinhibition is essential for developing specific modulators.

Purpose of the Study:

  • To elucidate the structural mechanism underlying the autoinhibition of Protein Kinase C beta II (PKCβII).
  • To propose an alternative structural model for PKCβII consistent with known regulatory mechanisms.
  • To identify key interactions responsible for maintaining PKC in an inactive conformation.

Main Methods:

  • Reinterpretation of existing crystal structures of PKCβII.
  • Computational docking analysis to predict protein interactions.
  • Site-directed mutagenesis to functionally validate predicted interactions.
  • Functional assays to assess the impact of mutations on PKC activity.

Main Results:

  • A novel autoinhibitory mechanism for PKCβII was proposed, involving intramolecular interactions.
  • The Ca(2+) -sensing C2 domain was identified to interact with the kinase domain and carboxyl-terminal tail, stabilizing an inactive state.
  • Mutagenesis confirmed the role of specific residues in mediating these interactions and maintaining autoinhibition.
  • Calcium-dependent membrane binding of the C2 domain was shown to be an initial step in PKC activation.

Conclusions:

  • The study reveals a detailed structural basis for PKCβII autoinhibition, mediated by the C2 domain.
  • This understanding provides a new framework for designing targeted therapies aimed at modulating PKC activity.
  • Elucidating the autoinhibitory mechanism opens avenues for developing drugs for cancer and neurodegenerative diseases.

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