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Cell Rep. 2015 Aug 25;12(8):1252-60. doi: 10.1016/j.celrep.2015.07.039. Epub 2015 Aug 13.

Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII.

Author information

1
Department 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.
2
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92037, USA.
3
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92037, USA. Electronic address: anewton@ucsd.edu.

Abstract

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. Ca(2+)-dependent bridging of the C2 domain to membranes provides the first step in activating PKC via conformational selection. Although the placement of the C1 domains remains to be determined, elucidation of the structural basis for autoinhibition of PKCβII unveils a unique direction for therapeutically targeting PKC.

PMID:
26279568
PMCID:
PMC4551583
DOI:
10.1016/j.celrep.2015.07.039
[Indexed for MEDLINE]
Free PMC Article

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