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J Biol Chem. 2014 Jun 20;289(25):17812-29. doi: 10.1074/jbc.M113.534750. Epub 2014 Apr 30.

Conserved modular domains team up to latch-open active protein kinase Cα.

Author information

1
From the Biophysics Program.
2
Department of Cell and Developmental Biology.
3
Department of Cell and Developmental Biology, Department of Cardiac Surgery.
4
Department of Biomedical Engineering, Life Sciences Institute, and.
5
From the Biophysics Program, the Departments of Pharmacology and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109.
6
Department of Cardiac Surgery, Department of Biomedical Engineering, Life Sciences Institute, and.
7
From the Biophysics Program, Department of Cell and Developmental Biology, Department of Biomedical Engineering, Life Sciences Institute, and sivaraj@umich.edu.

Abstract

Signaling proteins comprised of modular domains have evolved along with multicellularity as a method to facilitate increasing intracellular bandwidth. The effects of intramolecular interactions between modular domains within the context of native proteins have been largely unexplored. Here we examine intra- and intermolecular interactions in the multidomain signaling protein, protein kinase Cα (PKCα). We identify three interactions between two activated PKC molecules that synergistically stabilize a nanomolar affinity homodimer. Disruption of the homodimer results in a loss of PKC-mediated ERK1/2 phosphorylation, whereas disruption of the auto-inhibited state promotes the homodimer and prolongs PKC membrane localization. These observations support a novel regulatory mechanism wherein homodimerization dictates the equilibrium between the auto-inhibited and active states of PKC by sequestering auto-inhibitory interactions. Our findings underscore the physiological importance of context-dependent modular domain interactions in cell signaling.

KEYWORDS:

Extracellular Signal-regulated Kinase (ERK); Fluorescence Resonance Energy Transfer (FRET); Homodimerization; Modular Domains; PKC; Protein Domain; Protein Kinase C (PKC); Protein-Protein Interaction

PMID:
24790081
PMCID:
PMC4067214
DOI:
10.1074/jbc.M113.534750
[Indexed for MEDLINE]
Free PMC Article
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