Calmodulin, binding target

Small ubiquitous calcium-binding protein. Calmodulin binds and regulates the activity of many protein targets involved in cellular signal transduction pathways mediated by calcium. Calmodulin is ranked among the most conserved proteins and plays a key role in many cellular processes. 

Inositol trisphosphate opens a calcium transport channel in the membrane of the endoplasmic reticulum. This leads to an influx of calcium from storage in the endoplasmic reticulum and a 10-fold increase in the cytosolic concentration of calcium ions. Calmodulin is a small calcium binding protein found in all cells. Its affinity for calcium is such that, at the resting concentration of calcium in the cytosol (of the order of 0.1 /xmol per L), little or none is bound to calmodulin. When the cytosolic concentration of calcium rises to about 1 /xmol per L, as occurs in response to opening of the endoplasmic reticulum calcium transport channel, calmodulin binds 4 mol of calcium per mol of protein. When this occurs, calmodulin undergoes a conformational change, and calcium-calmodulin binds to, and activates, cytosolic protein kinases, which in turn phosphorylate target enzymes. 

Calcium ion acts by binding to calmodulin and other calcium sensors. Calmodulin contains four calcium-binding modules called EF hands that recur in other proteins. Ca2+-calmodulin activates target proteins by binding to positively charged amphipathic helices. 

Figure 14.16 Calmodulin binds to or helices. (A) An a helix (purple) in CaM kinase I is a target for calmodulin. (B) After Ca " binding (1), the two halves of calmodulin clamp down around the target helix (2), binding it through hydrophobic and ionic interactions. In CaM kinase I, this interaction allows the enzyme to adopt an active conformation. [Drawn from 1A06, ICFD. 1CLU and ICMl.pdb.]...

Fig. 6.13 Comparison of different Ca2+/Calmodu-lin structures (from Hoeflich and Ikura, 2002). The figure illustrates the different conformations of calmodulin when bound to target protein kinases. Calmodulin is shown in yellow and calcium ions are depicted in blue. The interaction with the calmodulin binding domain of the protein kinases is...

With the help of NMR measurement, it has been shown that the Ca2+/calmodulin complex has a flexible structure. Flexibility is probably of great importance for the function of Ca2+/calmodulin. Structural information on Ca2+/calmodulin bound to substrates is only available for peptides derived from target proteins. In the complex with peptide substrates (Fig. 6.13), Ca2+/calmodulin has a collapsed structure in which the two globular domains are much closer together than in free Ca2+/calmodulin, and it wraps around and sequesters the helical calmodulin-binding peptides. 

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