calmodulin

Calmodulin is a highly conserved, small acidic calcium-binding messenger protein found in all eukaryotic cells. It serves as an intracellular calcium sensor and signal transducer, translating fluctuations in intracellular Ca2+ into targeted cellular responses by modulating a broad range of enzymes and structural proteins.

The protein is composed of 149 amino acids per subunit and contains four EF-hand calcium-binding motifs arranged in two globular domains (N-terminal and C-terminal) connected by a flexible linker. In the absence of Ca2+, calmodulin adopts a closed conformation; when Ca2+ levels rise, binding induces a conformational change that exposes hydrophobic surfaces, enabling interaction with target peptides and proteins.

Calmodulin interacts with many enzymes and other proteins, including CaM-dependent kinases (such as CaMKs), calcineurin, myosin light-chain kinase, nitric oxide synthase, and phosphodiesterases, as well as various ion channels and transporters. Through these interactions, it regulates processes such as muscle contraction, neurotransmitter release, gene expression, metabolism, and cell cycle progression. The versatility of calmodulin stems from its ability to bind calcium and then recruit numerous diverse targets.

Genetically, calmodulin is encoded by three highly similar human genes—CALM1, CALM2, and CALM3—producing nearly identical protein sequences and broad tissue expression.

Clinical significance includes calmodulinopathies, disorders arising from CALM gene mutations that are associated with inherited, often severe, arrhythmias and sudden cardiac death, reflecting disrupted calcium sensing and signaling.

Calmodulin also features in research and biotechnology, notably as a component of calcium indicator tools such as GCaMP, which harness calmodulin’s calcium-dependent conformational change to report intracellular Ca2+ dynamics.