Using Markov State Models to Develop a Mechanistic Understanding of Protein Kinase A-RI{alpha} Activation in Response to cAMP Binding [Computational Biology]

September 8th, 2014 by Boras, B. W., Kornev, A., Taylor, S. S., McCulloch, A. D.

Protein Kinase A (PKA) holoenzyme consists of two catalytic (C)-subunits and two regulatory (R)-subunits (R2C2). The kinase is activated by the binding of two cAMP to the cyclic nucleotide binding domains (CBD), A and B, on each R-subunit. Despite extensive study, details of the allosteric mechanisms underlying the cooperativity of holoenzyme activation remain unknown. Several Markov State Models (MM) of PKA RIα were developed to test competing theories of activation for the R2C2 complex. We found that CBD-B plays an essential role in R-C interaction and promotes the release of the first C-subunit prior to the binding to CBD-A. This favors a conformational selection mechanism of release of the first C-subunit of PKA. However, the release of the second C-subunit requires all four cAMP sites to be occupied, similar to an induced fit mechanism. These analyses elucidate R-C heterodimer interactions in the cooperative activation of PKA and cAMP binding and represents a new mechanistic model of R2C2 PKA-RIα activation.
  • Posted in Journal of Biological Chemistry, Publications
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