75 another important ca 2 receptor protein is

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75 Another important Ca 2 + -receptor protein is troponin C (TnC), which occurs in muscle cells and is instrumental in mediating muscle contraction. 76 These two types of proteins are highly ho- mologous, as we shall see, and may be considered members of a superfamily of closely related intracellular Ca 2 + -binding proteins. This superfamily has been given the name' 'the calmodulin superfamily," and close to 200 distinct family members are presently known. 77 Not all members of the superfamily may qual- ify as Ca 2 + receptors; some like parvalbumins and calbindins (see Section IV.A) appear to have a role in intracellular transport and/or Ca 2+ -buffering. For oth- ers, such as the 5-100 proteins 78 found predominantly in brain tissue, and cal- cimedins,79 isolated from smooth muscle, the biological function is still unclear. One Ca 2 + receptor with enzymatic activity is protein kinase C. Its activity is markedly increased in the presence of Ca 2+ , and it has a high calcium-bind- ing constant (see Table 3.2) in the presence of diacylglycerol or phorbol es- ters. 80 During recent years, groups interested in the role of Ca 2 + in secretion and in the control of membrane cytoskeleton have identified some intracellular Ca 2+ / phospholipid-binding proteins that appear to be distinct from the calmodulin superfamily; these include lipocortin, endonexin, calelectrin, p36, and calpac- tin. 81-83 These membrane-binding proteins are collectively called annexins, 84 and contain repeated domains distinct from EF-hands. The Ca 2 + sites are very sim- ilar to that observed in phospholipase A 2 , as shown by the recently determined x-ray structure of annexin V. 172 A condensed overview of the interaction of Ca 2 + with intracellular proteins is shown in Figure 3.16. We will now go on to discuss the molecular properties of some of the proteins mentioned above, start- ing with calmodulin.
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136 ,/ ....... / // I -' / J. ~-' ;:;- r phosphorylated target proteins protein kinase C plasma membrane mitochondrion dephosphorylated target proteins muscle ...... l---- Troponin C -- ~ parvalbumins ro~"ct;oo /~ ~ C,','m,"" . . 1 :~:::eIlUlar secretion-regulating proteases proteins (calpain ... ) Ca 2 +/calmodulin- Ca 2 +-calmodulin calmodulin-activated or 00"/1'\" /1\ :;h~~~;~~o~o'Ym" 00' calmodulin-dependent protein kinases 01~ phosphorylated target protein Figure 3.16 Condensed overview of the interaction of Ca 2+ with intracellular proteins. A. Calmodulin Calmodulin is a small acidic protein (My = 16,700), the amino-acid sequence of which has been remarkably preserved during evolution. Early on, an analysis of its amino-acid sequence indicated that it should have four Ca 2+ -binding sites, a deduction that proved to be correct. The three-dimensional x-ray structure of bovine brain calmodulin 85 has been solved to a resolution of 2.2 A. A space- filling model is shown in Figure 3. 17. (See color plate section, page C-9.) The molecule has a dumbbell-like shape, with two globular domains connected by an eight-tum a-helix-an unusual structural feature. In the crystal structure, there are no direct contacts between the two globular domains, each of which contains two Ca 2+ -binding sites. The Ca
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