Why the study?
To probe the structural interaction between the membrane-proximal cytosolic C-terminal domain of CaV1.2 and calmodulin.
Demonstrates that calcium binding to the N-lobe of calmodulin induces a conformational change in the CaV1.2 C-terminal regulatory domain, providing mechanistic insight into calcium-dependent channel inactivation.
No immediate clinical impact; leaves open CaV1.2-CaM roles in cardiac excitability.
Calmodulin (CaM) binds to the membrane‐proximal cytosolic C‐terminal domain of Ca V 1.2 (residues 1520–1669, CT(1520–1669)) and causes Ca 2+ ‐induced conformational changes that promote Ca 2+ ‐dependent channel inactivation (CDI). We report biophysical studies that probe the structural interaction between CT(1520–1669) and CaM. The recombinantly expressed CT(1520–1669) is insoluble, but can be solubilized in the presence of Ca 2+ ‐saturated CaM (Ca 4 /CaM), but not in the presence of Ca 2+ ‐free CaM (apoCaM). We show that half‐calcified CaM (Ca 2 /CaM 12 ) forms a complex with CT(1520–1669) that is less soluble than CT(1520–1669) bound to Ca 4 /CaM. The NMR spectrum of CT(1520–1669) reveals spectral differences caused by the binding of Ca 2 /CaM 12 versus Ca 4 /CaM, suggesting that the binding of Ca 2+ to the CaM N‐lobe may induce a conformational change in CT(1520–1669).
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Yadav et al. (2022) studied this question.
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