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Calmodulin Page
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 phosphotases.[1][2][1]
Structure
Calmodulin is a small, highly conserved protein 148 amino acids long (16706 Daltons). 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. Each globular domain contains a pair of EF-hand motifs, which allows calmodulin to sense intracellular calcium levels by binding up to four Ca2+ ions. Calcium participates in an intracellular signaling system by acting as a diffusible second messenger to the initial stimuli.
Similarity to Troponin C
Calmodulin's structure is very similar to the structure of Troponin C (which is another calcium binding protein). They are both members of the EFh super family. Troponin C, like Calmodulin, has two globular domains that are connected by a linker region.[2] However, Troponin C and Calmodulin differ in the length of the linker region; the linker region of Calmodulin is smaller than that of Troponin C.[3] These remarkably similar structures are an example of how the EF hand motif is highly conserved in calcium binding proteins. Though they have similar structures, their functions are very different. Troponin C has a very specific function (to illicit a conformational change in Troponin I) ultimatley causing a contraction in skeletal muscles. Calmodulin, evolved to bind a wider variety of target proteins, allowing it to play a role in many physiological events.[4]
Importance of Flexibility in Calmodulin
Since Calmodulin binds such a wide variety of target proteins, it is 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.[2] (INSERT PICTURE FROM PDB???)
Mechanism
Overall
Up to four calcium ions are bound by calmodulin via its four EF hand motifs. EF hands supply an electronegative environment for ioncoordination. After calcium binding, hydrophobic methyl groups from methionine residues become exposed on the protein via conformational change. Using both X-Ray and NMR studies, scientists were able to determine that the conformational changes occured in the alpha-helices of the EF motif, which changes the binding affinity for target proteins. When the alpha helices are perpendicular to one another, the Calmodulin is in an open confirmation giving it a higher affinity for target proteins.[3] More specifically, this conformational change presents hydrophobic surfaces, which can in turn bind to Basic Amphiphilic Helices (BAA helices) on the target protein. These helices contain complementary hydrophobic regions. The flexibility of calmodulin's hinged region allows the molecule to wrap around its target. This property allows it to tightly bind to a wide range of different target proteins. The C-domain of calmodulin has a higher affinity for calcium than does the N-domain.
Dynamic features
Compared to the X-ray crystal structure, the C-terminal domain solution structure is similar while the EF hands of the N-terminal domain are considerably less open. The backbone flexibility within calmodulin is key to its ability to bind a wide range of targets.[4] Protein domains, connected by intrinsically disordered flexible linker domains, induce long-range allostery via protein domain dynamics.
