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 (the N- and C- domains) each containing a pair of EF hand motifs separated by a flexible linker region for a total of four Ca2+ binding sites, two in each globular domain. In the Ca2+-free state, the helices that form the four EF-hands are collapsed in a compact orientation, and the central linker is disordered; in the Ca2+-saturated state, the EF-hand helices adopt an open orientation roughly perpendicular to one another, and the central linker forms an extended alpha-helix in the crystal structure, but remains largely disordered in solution. The C-domain has a higher binding affinity for Ca2+ than the N-domain. Calmodulin is structurally quite similar to troponin C, another Ca2+-binding protein containing four EF-hand motifs. However, troponin C contains an additional alpha-helix at its N-terminus, and is constitutively bound to its target, troponin I. It therefore does not exhibit the same diversity of target recognition as does calmodulin. Calmodulin's ability to recognize a tremendous range of target proteins is due in large part to its structural flexibility. In addition to the flexibility of the central linker domain, the N- and C-domains undergo open-closed conformational cycling in the Ca2+-bound state. Calmodulin also exhibits great structural variability, and undergoes considerable conformational fluctuations, when bound to targets.