Allosteric linkers in cAMP signalling

Madoka Akimoto, Kody Moleschi, Stephen Boulton, Bryan VanSchouwen, Rajeevan Selvaratnam, Susan S. Taylor, Giuseppe Melacini

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Weak interactions mediated by dynamic linkers are key determinants of allosteric regulation in multidomain signalling proteins. However, the mechanisms of linker-dependent control have remained largely elusive. In the present article, we review an allosteric model introduced recently to explain how signalling proteins effectively sense and respond to weak interactions, such as those elicited by flexible linkers flanking globular domains. Central to this model is the idea that near degeneracy within the free energy landscape of conformational selection maximally amplifies the response to weak (∼2RT), but conformation-selective interactions. The model was tested as proof of principle using the prototypical regulatory subunit (R) of protein kinase A and led to the unanticipated finding that dynamic linkers control kinase activation and inhibition by tuning the inhibitory pre-equilibrium of a minimally populated intermediate (apo R). A practical implication of the proposed model is a new strategy to design kinase inhibitors with enhanced potency through frustration-relieving mutations.

Original languageEnglish (US)
Pages (from-to)139-144
Number of pages6
JournalBiochemical Society transactions
Issue number1
StatePublished - Feb 2014


  • Allostery
  • CAMP
  • CGMP
  • Covariance
  • NMR
  • Protein dynamics
  • Singular value decomposition (SVD)


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