Calmodulin

Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca²⁺, and the binding of Ca²⁺ is required for the activation of Calmodulin. Once bound to Ca²⁺, Calmodulin acts as part of a calcium signal transduction pathway by modifying its interactions with various target proteins such as kinases or phosphatases.

Calmodulin is a small, highly conserved protein that is 148 amino acids long (16.7 KDa). The protein has two approximately symmetrical globular domains each containing a pair of EF-hand motifs (the N- and C-domain) separated by a flexible linker region for a total of four Ca²⁺ binding sites. Each EF-hand motif allows calmodulin to sense intracellular calcium levels by binding one Ca²⁺ ion. Calcium ion binding regions are found in the following positions in the sequence of amino acids: 21-32, 57-68, 94-105 and 130-141; each region that calcium binds to is exactly 12 amino acids long. These regions are located between two alpha helices in the EF-hand motifs, the first two regions (21-32 and 57-68) are on one side of the linker region the other two (94-105 and 130-141) are on the other side.

Calmodulin binds such a wide variety of target proteins, making it especially important for it to have flexibility. Though Calmodulin's flexibility is more evident when it is bound to a target protein, NMR studies have shown that the linker region of Calmodulin is flexible, even when it is not bound to a target protein. Another important characteristic of calmodulin that allows it to bind a large variety of target proteins is the generic shape of the non-polar grooves in the binding sites. Since the non-polar grooves are generic, they don't require the target proteins to have any specific sequence of amino acids allowing a larger variety of target proteins to be bound. Together, these two structural characteristics of calmodulin allow it to flexibly bind target proteins with various shapes and amino acid sequences. For example, calmodulin binds both NMDA receptors and potassium channels which differ in length by about 50 amino acid residues.

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