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Discovery of allostery in PKA signaling

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Abstract

Cyclic AMP (cAMP)-dependent protein kinase (PKA) was the second protein kinase to be identified, and the PKA catalytic (C)-subunit serves as a prototype for the large protein kinase superfamily that contains over 500 gene products. The protein kinases regulate many biological functions in eukaryotic cells and are now also a major therapeutic target. The discovery of PKA nearly 50 years ago was quickly followed by the identification of the regulatory subunits that bind cAMP and release the catalytic activity from the holoenzyme. Thus in PKA we see the convergence of two major signaling mechanisms—protein phosphorylation and second messenger signaling through cAMP. Crystallography provides a foundation for understanding function, and detailed knowledge of the structure of the isolated regulatory (R)- and catalytic (C)-subunits has been extremely informative. Yet it is the R2C2 holoenzyme that predominates in cells, and the allosteric features of PKA signaling can only be fully appreciated by seeing the full-length protein. The symmetry and the quaternary constraints that one R:C heterodimer exerts on the other in the holoenzyme simply are not present in the isolated subunits or even in the R:C heterodimer.

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Acknowledgments

We acknowledge the Taylor laboratory whose members have for many years carried out the interdisciplinary work, both structural and biochemical, that has allowed us to achieve an understanding of these proteins. We especially acknowledge earlier discussions and encouragement from Professor Shmuel Shaltiel, the Weizmann Institute, who never let us forget the importance of the holoenzyme after we solved the first crystal structures of the C-subunit. We are also enormously grateful for discussions and encouragement and guidance from Professor Jean Pierre Changeux whose visits to UCSD over the past 7 years have helped us to understand and appreciate and, hopefully in the end, to visualize the mechanistic details of the allosteric activation of PKA. Obviously we are all still learning and challenges remain!

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Funding

This study was funded by NIH grants GM34921 and GM19301 to SST and from the Howard Hughes Medical Institute to SST.

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human or animal subjects performed by the author, with the exception of those carried out on electric fish.

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Authors and Affiliations

  1. Department of Pharmacology, University of California at San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0654, USA

    Ping Zhang, Alexandr P. Kornev, Jian Wu & Susan S. Taylor

  2. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, 92093, USA

    Susan S. Taylor

Authors
  1. Ping Zhang
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  2. Alexandr P. Kornev
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  3. Jian Wu
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  4. Susan S. Taylor
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Corresponding author

Correspondence to Susan S. Taylor.

Additional information

This article is part of a Special Issue on ‘The Role of Protein Dynamics in Allosteric Effects’ edited by Gordon Roberts.

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Zhang, P., Kornev, A.P., Wu, J. et al. Discovery of allostery in PKA signaling. Biophys Rev 7, 227–238 (2015). https://doi.org/10.1007/s12551-015-0170-x

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