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Evolution of allostery in the cyclic nucleotide binding module

Natarajan Kannan1, Jian Wu1, Ganesh S Anand2, Shibu Yooseph3, Andrew F Neuwald4, J Craig Venter3 and Susan S Taylor5*

Author Affiliations

1 Department of Chemistry and Biochemistry, University of California, Gilman Drive, La Jolla, California, 92093-0654, USA

2 Department of Biological Sciences, Science Drive 4, National University of Singapore, Singapore 117543

3 J Craig Venter Institute, Medical Center Drive, Rockville, MD 20850, USA

4 Institute for Genome Sciences and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, HSF-II, Penn Street, Baltimore, MD 21201, USA

5 Department of Chemistry and Biochemistry, and HHMI, University of California, Gilman Drive, La Jolla, California, 92093-0654, USA

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Genome Biology 2007, 8:R264  doi:10.1186/gb-2007-8-12-r264

Published: 12 December 2007



The cyclic nucleotide binding (CNB) domain regulates signaling pathways in both eukaryotes and prokaryotes. In this study, we analyze the evolutionary information embedded in genomic sequences to explore the diversity of signaling through the CNB domain and also how the CNB domain elicits a cellular response upon binding to cAMP.


Identification and classification of CNB domains in Global Ocean Sampling and other protein sequences reveals that they typically are fused to a wide variety of functional domains. CNB domains have undergone major sequence variation during evolution. In particular, the sequence motif that anchors the cAMP phosphate (termed the PBC motif) is strikingly different in some families. This variation may contribute to ligand specificity inasmuch as members of the prokaryotic cooA family, for example, harbor a CNB domain that contains a non-canonical PBC motif and that binds a heme ligand in the cAMP binding pocket. Statistical comparison of the functional constraints imposed on the canonical and non-canonical PBC containing sequences reveals that a key arginine, which coordinates with the cAMP phosphate, has co-evolved with a glycine in a distal β2-β3 loop that allosterically couples cAMP binding to distal regulatory sites.


Our analysis suggests that CNB domains have evolved as a scaffold to sense a wide variety of second messenger signals. Based on sequence, structural and biochemical data, we propose a mechanism for allosteric regulation by CNB domains.