135136 the findings are quite unexpected v molecular

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135,136 The findings are quite unexpected.
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V. MOLECULAR ASPECTS OF Ca 2 + -REGULATED INTRACELLULAR PROCESSES 149 The protein contains four distinct domains. The first and third domains have no clear sequence homologies with known protein sequences, but the second do- main has a high homology with the proteolytic enzyme papain, and the fourth domain is highly homologous to calmodulin. This fourth domain thus has four EF-hand-type Ca 2 + -binding sites, although the third site has a somewhat un- usual loqp sequence. Here we apparently are faced with an unusual invention by Nature: by fusing the gene for a protease with that of the canonical Ca 2 + receptor, she has created a molecule in which a regulatory protein is covalently linked to its target enzyme! G. Protein Kinase C Before we leave our brief survey of intracellular Ca 2+ -binding proteins, we must write a few lines about an important Ca 2+ -regulated kinase (a phospho- rylating enzyme), i.e., protein kinase C (PKC). The activity of this enzyme, or rather family of enzymes, 137 appears to be regulated by three factors: phospho- lipids, in particular phosphatidylserine; diacyl-glycerols, one of the products of inositol lipid breakdown; and Ca 2+ ions. The high-activity form of PKC, which appears responsible for much of the phosphorylation activity of many cells, is presumably membrane-bound, whereas the low-activity form may be partly cy- tosolic (Figure 3.27). The schematic structure of rabbit PKC (M r = 77 kDa) inactive forms of protein kinase C + Ca 2 + ll- ca2 + active form of protein kinase C phosphorylated protein Figure 3.27 Outline of the cellular events that result in the activation of protein kinase C (PKC). The en- zyme apparently exists in at least two states. Recent sequence work indicates that it has a Ca 2+_ binding site of the EF-hand type. When no Ca 2+ ion is bound, and when the "concentration" of diacylglycerol (DG) in the inner layer of the plasma membrane is low, the kinase exists in a low-activity form, possibly dissociated from the membrane. When a hormone binds to a plasma- membrane receptor (R), cleavage of phosphoinositol into 1,4,5-IP 3 and DG is induced. The lat- ter lipid may bind to and activate the calcium-loaded form of PKC. The active form of protein kinase C will now phosphorylate other cytoplasmic proteins, and in this way modify their bio- chemical properties. R = receptor; PL-C = phospholipase C; G = a GTP-binding protein that is assumed to act as an intermediary between the receptor and the membrane bound PL-C.
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150 protein kinase 1~ .. r_eg=-U_la_to_rY=--do_m_a_in -+-~ 11~ .. __ d_o_m_a_in -----j~~1 ATP binding site catalytic site & target recognition(?) Figure 3.28 Schematic representation of the structure of rabbit protein kinase C. 138 Three highly homologous protein kinases C were actually identified with M r = 76,800. The kinase region shows clear similarity with other kinases. The regulatory domain should contain binding sites for Ca 2 +, phosphatidyl serine (PS), and diacylglycerol (DG).
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