Calmodulin target enzymes

Meador, W.E., Means, A.R., Quiocho, F.A. Target enzyme recognition by calmodulin 2.4 A stmcture of a calmodulin-peptide complex. Science 257 1251-1255, 1992. 

Calcium can also directly affect signaling through another pathway. The major calcium binding protein in the cell is calmodulin (CAM). CAM is not an enzyme, but it will activate some enzymes when it binds to them. CAM binds to its target enzymes only when calcium is bound... 

TFP has been widely studied in this regard, and a number of structural studies have indicated the binding of one, two, three, or four TFP molecules to calmodulin in the hydrophobic pockets where target enzymes would also bind. Most studies in solution have indicated that CaM has two high-affinity... 

Many more structure determinations of CaM-binding peptides have been carried out. For instance, the NMR structure determined by Ikura and co-workers for a CaM/CaMKK (from rat) complex (PDB ICKK) shows a calmodulin collapsed structure similar to those of CaM/smMLCK, CaM/ skMLCK, and CaM/CaMKIIa with the rCaMKK peptide cradled between calmodulin s C- and N-terminal domains. However, two features are different for CaM/rCaMKK. The first is that the peptide is bound in an inverted position compared to the others—that is, the N-terminal end of the rCaMKK peptide binds to CaM s N-terminal end and the C-terminal end binds to the C-terminal end rather than vice versa. This factor appears related to the clusters of basic residues on the target enzyme binding peptide—that is, when the... 

An example for the reversible association of activator proteins with an enzyme is the Ca -calmodulin dependent enzymes. Calmodulin is a Ca -binding protein which can activate target enzymes, e.g. phosphorylase kinase (see 6.7.1 and 7.4) in its Ca -boimd form. Another example for activating proteins is the cyclins (see chapter 14). The cyc-lins are activators of protein kinases that regulate the cell cycle. 

Secondly, a calcium binding protein could function as a calcium dependent regulatory protein. A typical example is calmodulin (for a review see Ref. 17) at resting [Ca2+]j, this protein is inactive but during activation of the calcium signal the protein binds calcium and activates several target enzymes and proteins. 

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. 

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