The Role of Regulatory Domains in Maintaining Auto-inhibition in the Multi-Domain Kinase PKC{alpha} [Enzymology]

Resolving the conformational dynamics of large multi-domain proteins has proven to be a significant challenge. Here we use a variety of techniques to dissect the individual roles of Protein Kinase Cα's (PKCα) regulatory domains in maintaining catalytic auto-inhibition. We find that while the pseudosubstrate domain is necessary for auto-inhibition 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 auto-inhibited interaction and increases basal activity. Modulating this interaction between the catalytic and regulatory domains reveals a direct correlation between auto-inhibition and membrane translocation following PKC activation.

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