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.
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February 2014
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Conference Article|
January 23 2014
Allosteric linkers in cAMP signalling
Madoka Akimoto;
Madoka Akimoto
*Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1
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Kody Moleschi;
Kody Moleschi
*Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1
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Stephen Boulton;
Stephen Boulton
†Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1
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Bryan VanSchouwen;
Bryan VanSchouwen
*Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1
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Rajeevan Selvaratnam;
Rajeevan Selvaratnam
*Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1
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Susan S. Taylor;
Susan S. Taylor
‡Howard Hughes Medical Institute, University of California, La Jolla, CA 92093, U.S.A.
§Department of Chemistry and Biochemistry, University of California, La Jolla, CA 92093, U.S.A.
∥Department of Pharmacology, University of California, La Jolla, CA 92093, U.S.A.
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Giuseppe Melacini
Giuseppe Melacini
1
*Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1
†Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1
1To whom correspondence should be addressed (email melacin@mcmaster.ca).
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Publisher: Portland Press Ltd
Received:
November 13 2013
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem Soc Trans (2014) 42 (1): 139–144.
Article history
Received:
November 13 2013
Citation
Madoka Akimoto, Kody Moleschi, Stephen Boulton, Bryan VanSchouwen, Rajeevan Selvaratnam, Susan S. Taylor, Giuseppe Melacini; Allosteric linkers in cAMP signalling. Biochem Soc Trans 1 February 2014; 42 (1): 139–144. doi: https://doi.org/10.1042/BST20130257
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