Epac (exchange protein directly activated by cAMP) is a critical cAMP receptor, which senses cAMP and couples the cAMP signal to the catalysis of guanine exchange in the Rap substrate. In the present paper, we review the NMR studies that we have undertaken on the CBD (cyclic-nucleotide-binding domain) of Epac1. Our NMR investigations have shown that cAMP controls distal autoinhibitory interactions through long-range modulations in dynamics. Such dynamically mediated allosteric effects contribute not only to the cAMP-dependent activation of Epac, but also to the selectivity of Epac for cAMP in contrast with cGMP. In addition, we have mapped the interaction networks that couple the cAMP-binding site to the sites involved in the autoinhibitory interactions, using a method based on the covariance analysis of NMR chemical shifts. We anticipate that this approach is generally applicable to dissect allosteric networks in signalling domains.
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February 2012
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Conference Article|
January 19 2012
cAMP-dependent allostery and dynamics in Epac: an NMR view
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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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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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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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:
June 16 2011
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (1): 219–223.
Article history
Received:
June 16 2011
Citation
Rajeevan Selvaratnam, Madoka Akimoto, Bryan VanSchouwen, Giuseppe Melacini; cAMP-dependent allostery and dynamics in Epac: an NMR view. Biochem Soc Trans 1 February 2012; 40 (1): 219–223. doi: https://doi.org/10.1042/BST20110628
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