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Intramolecular C2‐Kinase Domain Interactions Autoinhibit Conventional Protein Kinase
Author(s) -
Callender Julia A,
Antal Corina E,
Kornev Alexandr P,
Yang Yuan,
Igumenova Tatyana I,
Taylor Susan S,
Newton Alexandra C
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1115.2
Subject(s) - protein kinase c , isozyme , protein kinase domain , kinase , chemistry , microbiology and biotechnology , enzyme , biochemistry , biophysics , computational biology , biology , gene , mutant
The signaling output of protein kinase C (PKC) is exquisitely controlled, with its disruption resulting in pathophysiologies. Identifying the structural basis for autoinhibition is central to developing effective therapies for cancer, where PKC activity needs to be enhanced, or neurodegenerative diseases, where PKC activity should be inhibited. Here, we reinterpret a previously reported crystal structure of PKCβII and use docking and functional analysis to propose an alternative structure that is consistent with previous literature on PKC regulation. Mutagenesis of predicted contact residues establishes that the Ca 2+ ‐sensing C2 domain interacts intramolecularly with the kinase domain and the carboxyl‐terminal tail, locking PKC in an inactive conformation. Applying a similar approach towards another conventional PKC isozyme, PKCα, confirmed C2 domain‐mediated autoinhibition as a shared mechanism among conventional PKC isozymes. Ca 2+ ‐dependent bridging of the C2 domain to membranes provides the first step in activating PKC via conformational selection. Therefore, elucidation of the structural basis for autoinhibition of PKC unveils a unique direction for therapeutically targeting PKC activity. Support or Funding Information This work was supported by NIH grants GM43154 to A.C.N. and DK54441 to A.C.N. and S.S.T. C.E.A. was supported in part by the University of California, San Diego, Graduate Training Program in Cellular and Molecular Pharmacology (T32 GM007752) and the National Science Foundation Graduate Research Fellowship (DGE1144086).