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

Author

Listed:
  • 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
    Baylor College of Medicine
    The University of Texas MD Anderson Cancer Center
    Rice University)

  • Susan S. Taylor

    (University of California, San Diego
    University of California, San Diego)

  • Rodrigo A. Maillard

    (Georgetown University)

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.

Suggested Citation

  • Yuxin Hao & Jeneffer P. England & Luca Bellucci & Emanuele Paci & H. Courtney Hodges & Susan S. Taylor & Rodrigo A. Maillard, 2019. "Activation of PKA via asymmetric allosteric coupling of structurally conserved cyclic nucleotide binding domains," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11930-2
    DOI: 10.1038/s41467-019-11930-2
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    Cited by:

    1. Sahar Foroutannejad & Lydia L. Good & Changfan Lin & Zachariah I. Carter & Mahlet G. Tadesse & Aaron L. Lucius & Brian R. Crane & Rodrigo A. Maillard, 2023. "The cofactor-dependent folding mechanism of Drosophila cryptochrome revealed by single-molecule pulling experiments," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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