Activation of a Protein Kinase Via Asymmetric Allosteric Coupling of Structurally Conserved Signaling Modules
Yuxin Hao, Jeneffer England, Luca Belluci, Emanuele Paci, H. Courtney Hodges, Susan S. Taylor and Rodrigo A. Maillard
Received Date: 10th April 19
Cyclic nucleotide binding (CNB) domains are universally conserved signaling modules that regulate the activities of diverse protein functions. Yet, the structural and dynamic features that enable the cyclic nucleotide binding signal to allosterically regulate other functional domains remain unknown. We use force spectroscopy and molecular dynamics to monitor in real time the pathways of signals transduced by cAMP binding in protein kinase A (PKA). Despite being structurally conserved, we find that the response of the folding energy landscape to cAMP is domain-specific, resulting in unique but mutually coordinated regulatory tasks: one CNB domain initiates cAMP binding and cooperativity, while the other triggers inter-domain interactions that lock the active conformation. Moreover, we identify a new cAMP-responsive switch, whose stability and conformation depends on cAMP occupancy. Through mutagenesis and nucleotide analogs we show that this dynamic switch serves as a signaling hub, a previously unidentified role that amplifies the cAMP binding signal during the allosteric activation of PKA.
Read in full at bioRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.