Structural insights into calmodulin/adenylyl cyclase 8 interaction

Herbst, Sabine; Masada, Nana; Pfennig, Sabrina; Ihling, Christian H.; Cooper, Dermot M. F.; Sinz, Andrea
November 2013
Analytical & Bioanalytical Chemistry;Nov2013, Vol. 405 Issue 27, p9333
Academic Journal
Calmodulin (CaM) is a highly conserved intracellular Ca 2+-binding protein that exerts important functions in many cellular processes. Prominent examples of CaM-regulated proteins are adenylyl cyclases (ACs), which synthesize cAMP as a central second messenger. The interaction of ACs with CaM represents the link between Ca 2+-signaling and cAMP-signaling pathways. Thereby, different AC isoforms stimulated by CaM, comprise diverse mechanisms of regulation by the Ca 2+ sensor. To extend the structural information about the detailed mechanisms underlying the regulation of AC8 by CaM, we employed an integrated approach combining chemical cross-linking and mass spectrometry with two peptides representing the CaM-binding regions of AC8. These experiments reveal that the structures of CaM/AC8 peptide complexes are similar to that of the CaM/skeletal muscle myosin light chain kinase peptide complex where CaM is collapsed around the target peptide that binds to CaM in an antiparallel orientation. Cross-linking experiments were complemented by investigating the binding of AC8 peptides to CaM thermodynamically with isothermal titration calorimetry. There were no hints on a complex, in which both AC8 peptides bind simultaneously to CaM, refining our current understanding of the interaction between CaM and AC8. [Figure not available: see fulltext.]


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