Cell Reports
Volume 12, Issue 8, 25 August 2015, Pages 1252-1260
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Report
Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII

https://doi.org/10.1016/j.celrep.2015.07.039Get rights and content
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Highlights

  • The C2 domain of PKCβII interfaces with its kinase domain and C-terminal tail

  • The C2:kinase domain interaction is intramolecular and autoinhibitory

  • Open PKC conformation is selected upon membrane binding of the Ca2+-bound C2 domain

  • This study suggests a unique approach for therapeutically targeting PKCβII

Summary

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 Ca2+-sensing C2 domain interacts intramolecularly with the kinase domain and the carboxyl-terminal tail, locking PKC in an inactive conformation. Ca2+-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.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).