Activation of PKA via asymmetric allosteric coupling of structurally conserved cyclic nucleotide binding domains

Yuxin Hao, Jeneffer P. England, Luca Bellucci, Emanuele Paci, H. Courtney Hodges, Susan S. Taylor and Rodrigo A. Maillard ()
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Yuxin Hao: Georgetown University
Jeneffer P. England: Georgetown University
Luca Bellucci: NEST, Istituto Nanoscienze del CNR and Scuola Normale Superiore
Emanuele Paci: University of Leeds
H. Courtney Hodges: Baylor College of Medicine
Susan S. Taylor: University of California, San Diego
Rodrigo A. Maillard: Georgetown University

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Cyclic nucleotide-binding (CNB) domains allosterically regulate the activity of proteins with diverse functions, but the mechanisms that enable the cyclic nucleotide-binding signal to regulate distant domains are not well understood. Here we use optical tweezers and molecular dynamics to dissect changes in folding energy landscape associated with cAMP-binding signals transduced between the two CNB domains of protein kinase A (PKA). We find that the response of the energy landscape upon cAMP binding is domain specific, resulting in unique but mutually coordinated tasks: one CNB domain initiates cAMP binding and cooperativity, whereas the other triggers inter-domain interactions that promote the active conformation. Inter-domain interactions occur in a stepwise manner, beginning in intermediate-liganded states between apo and cAMP-bound domains. Moreover, we identify a cAMP-responsive switch, the N3A motif, whose conformation and stability depend on cAMP occupancy. This switch serves as a signaling hub, amplifying cAMP-binding signals during PKA activation.

Date: 2019
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DOI: 10.1038/s41467-019-11930-2

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