As its name suggests, calmodulin is a CALcium MODULated proteIN. It is abundant in the cytoplasm of all higher cells and has been highly conserved through evolution. Calmodulin acts as an intermediary protein that senses calcium levels and relays signals to various calcium-sensitive enzymes, ion channels and other proteins. It is a small protein composed of two globular domains connected together by a flexible linker; each end binds to two calcium ions.

Calmodulin contains four nearly identical high-affinity calcium binding sites. The calcium-binding motif is comprised of a characteristic loop flanked by two alpha helices. The positively-charged calcium ion is surrounded in the loop by negatively-charged sidechains of three aspartates and one glutamate, as well as one oxygen atom from the backbone of the protein chain.

Calmodulin's target proteins come in various shapes, sizes and sequences and are involved in a wide array of functions. Calmodulin binds and activates kinases and phosphatases that play significant roles in cell signaling, ion transport and cell death. One common theme in the contact between calmodulin and its different target proteins is the use of nonpolar interactions, through the unusually abundant methionines of calmodulin. Calcium binding exposes these nonpolar surfaces of calmodulin, which then bind to non-polar regions on the target proteins. These nonpolar areas form two neat grooves when calcium binds, waiting to grip the target protein. Because these nonpolar grooves are generic in shape, calmodulin acts as a versatile regulatory protein and its targets are not required to possess any specific amino acid sequence or structural binding motifs.

NMR studies show that the connector between the two calcium binding globular domains is flexible even when it is not bound to its target proteins. However, the full range of flexibility can be seen in calmodulin's interactions with its target proteins: in fact, calmodulin typically wraps around its target, with the two globular domains gripping either side of it.

Single fluorescent protein-based biosensors