An NMR portrait of functional and dysfunctional allosteric cooperativity in cAMP-dependent protein kinase A

Cristina Olivieri, Caitlin E Walker, Manu Veliparambil Subrahmanian, Fernando Porcelli, Susan S. Taylor, David A. Bernlohr, Gianluigi Veglia

Research output: Contribution to journalReview articlepeer-review

4 Scopus citations


The cAMP-dependent protein kinase A (PKA) is the archetypical eukaryotic kinase. The catalytic subunit (PKA-C) structure is highly conserved among the AGC-kinase family. PKA-C is a bilobal enzyme with a dynamic N-lobe, harbouring the Adenosine-5′-triphosphate (ATP) binding site and a more rigid helical C-lobe. The substrate-binding groove resides at the interface of the two lobes. A distinct feature of PKA-C is the positive binding cooperativity between nucleotide and substrate. Several PKA-C mutations lead to the development of adenocarcinomas, myxomas, and other rare forms of liver tumours. Nuclear magnetic resonance (NMR) spectroscopy shows that these mutations disrupt the allosteric communication between the two lobes, causing a drastic decrease in binding cooperativity. The loss of cooperativity correlates with changes in substrate fidelity and reduced kinase affinity for the endogenous protein kinase inhibitor (PKI). The similarity between PKI and the inhibitory sequence of the kinase regulatory subunits suggests that the overall mechanism of regulation of the kinase may be disrupted. We surmise that a reduced or obliterated cooperativity may constitute a common trait for both orthosteric and allosteric mutations of PKA-C that may lead to dysregulation and disease.

Original languageEnglish (US)
Pages (from-to)1055-1072
Number of pages18
JournalFEBS Letters
Issue number8
StatePublished - Apr 2023

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health, GM100310, HL144130 (GV), and the American Heart Association, 20PRE35120253 (CW).

Publisher Copyright:
© 2023 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.


  • NMR
  • allosteric regulation
  • conformational entropy
  • cooperativity
  • protein kinases

PubMed: MeSH publication types

  • Journal Article
  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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