Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 7, Pages 2873-2880Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.768457
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Funding
- American Heart Association Scientist Development Grant [13SDG14270009]
- National Institutes of Health [1DP2 CA186752-01, 1-R01-GM-105646-01-A1]
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Resolving the conformational dynamics of large multidomain proteins has proven to be a significant challenge. Here we use a variety of techniques to dissect the roles of individual protein kinase C alpha (PKC alpha) regulatory domains in maintaining catalytic autoinhibition. We find that whereas the pseudosubstrate domain is necessary for autoinhibition it is not sufficient. Instead, each regulatory domain (C1a, C1b, and C2) appears to strengthen the pseudosubstrate- catalytic domain interaction in a nucleotide- dependent manner. The pseudosubstrate and C1a domains, however, are minimally essential for maintaining the inactivated state. Furthermore, disrupting known interactions between the C1a and other regulatory domains releases the autoinhibited interaction and increases basal activity. Modulating this interaction between the catalytic and regulatory domains reveals a direct correlation between autoinhibition and membrane translocation following PKC activation.
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