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Length and Flexibility of the Disordered Tether Region of the PKA Regulatory Subunit Modulates Phosphorylation Kinetics of PKA within an AKAP Complex
Author(s) -
Rigatti Marc,
Michalski Paul,
Moraru Ion,
DodgeKafka Kimberly
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.881.10
Subject(s) - phosphorylation , allosteric regulation , protein subunit , protein kinase a , biophysics , flexibility (engineering) , chemistry , substrate (aquarium) , microbiology and biotechnology , kinase , scaffold protein , biochemistry , enzyme , biology , signal transduction , gene , ecology , statistics , mathematics
Protein Kinase A (PKA) is a ubiquitious kinase with over 200 known substrates. Targeting of PKA phosphorylation to a particular substrate is thought to occur via scaffolding by A Kinase Anchoring Proteins (AKAPs) however, the mechanism of such targeting is not completely understood. The widely accepted mechanism of PKA signaling involves the release of the catalytic subunit upon binding of cAMP to two allosteric sites on the regulatory subunit. Recent work by Smith et.al. (eLife 2013) demonstrates that the catalytic subunit of PKA within an AKAP complex may not actually be released upon stimulation of cAMP production. Further, they have shown that truncation of the unstructured tether region increases phosphorylation of substrates within the AKAP complex. Using Langevin Dynamics simulations we have investigated the contribution of both length and flexibility of this tethered region to phosphorylation of accessible substrates within the AKAP complex. Our simulation results indicate that flexibility of the tether region is necessary for the catalytic subunit to encounter its substrate and that the length of the tether defines the region of space that the catalytic subunit may explore. Shortening the tether length increases the probability of substrate binding and phosphorylation. Our results are consistent with the work of Smith et. al. and offer a mechanistic explanation for the contribution of tether length to substrate phosphorylation.