One of the best-studied CaM-kinases is CaM-kinase II, which is found in most animal cells but is especially enriched in the nervous system. It constitutes up to 2% of the total protein mass in some regions of the brain, and it is highly concentrated in synapses. CaM-kinase II has several remarkable properties. To begin with, it has a spectacular quaternary structure: twelve copies of the enzyme are assembled into a stacked pair of rings, with kinase domains on the outside linked to a central hub (Figure 15–34). This structure helps the enzyme function as a molecular memory device, switching to an active state when exposed to Ca2+/ calmodulin and then remaining active even after the Ca2+ signal has decayed. This is because adjacent kinase subunits can phosphorylate each other (a process called autophosphorylation) when Ca2+/calmodulin activates them (Figure 15–34). Once a kinase subunit is autophosphorylated, it remains active even in the absence of Ca2+, thereby prolonging the duration of the kinase activity beyond that of the initial activating Ca2+ signal. The enzyme maintains this activity until a protein phosphatase removes the autophosphorylation and shuts the kinase off. CaM-kinase II activation can thereby serve as a memory trace of a prior Ca2+ pulse, and it seems to have a role in some types of memory and learning in the vertebrate nervous system. Mutant mice that lack a brain-specific form of the enzyme have specific defects in their ability to remember where things are.
Figure 15–33 The structure of  Ca2+/calmodulin. (A) The molecule has a dumbbell shape, with two globular ends, which can bind to many target proteins. The globular ends are connected by a long, exposed α helix, which allows the protein to adopt a number of different conformations, depending on the target protein it interacts with. Each globular head has two Ca2+binding sites (Movie 15.6). (B) Shown is the major structural change that occurs in Ca2+/calmodulin when it binds to a target protein (in this example, a peptide that consists of the Ca2+/calmodulin-binding domain of a Ca2+/calmodulin-dependent protein kinase). Note that the  Ca2+/calmodulin has “jack-knifed” to surround the peptide. When it binds to other targets, it can adopt different conformations. (A, based on x-ray crystallographic data from Y.S. Babu et al., Nature 315:37–40, 1985. With permission from Macmillan Publishers Ltd; B, based  on x-ray crystallographic data from
W.E. Meador, A.R. Means, and
F.A. Quiocho, Science 257:1251–1255, 1992, and on nuclear magnetic resonance (NMR) spectroscopy data from M. Ikura et al., Science 256:632–638, 1992.)