Calcium and GTP Are Widely Used to Modulate Protein Activity

In the preceding examples, oxygen, cAMP, and ATP cause allosteric changes in the activity of their target proteins (hemoglobin, protein kinase A, and GroEL, respectively). Two additional allosteric ligands, Ca2+ and GTP, act through two types of ubiquitous proteins to regulate many cellular processes.

Calmodulin-Mediated Switching The concentration of Ca2+ free in the cytosol is kept very low («10~7 M) by membrane transport proteins that continually pump Ca2+ out of the cell or into the endoplasmic reticulum. As we learn in Chapter 7, the cytosolic Ca2+ level can increase from 10- to

100-fold by the release of Ca2+ from ER stores or by its import from the extracellular environment. This rise in cytosolic Ca2+ is sensed by Ca2 + -binding proteins, particularly those of the EF hand family, all of which contain the helix-loop-helix motif discussed earlier (see Figure 3-6a).

The prototype EF hand protein, calmodulin, is found in all eukaryotic cells and may exist as an individual monomeric protein or as a subunit of a multimeric protein. A dumbbell-shaped molecule, calmodulin contains four Ca2+-binding sites with a KDof «10 6 M. The binding of Ca2+ to calmodulin causes a conformational change that permits Ca2+/calmodulin to bind various target proteins, thereby switching their activity on or off (Figure 3-28). Calmodulin and similar EF hand proteins thus function as switch proteins, acting in concert with Ca2+ to modulate the activity of other proteins.

Switching Mediated by Guanine Nucleotide-Binding Proteins Another group of intracellular switch proteins constitutes the GTPase superfamily. These proteins include monomeric Ras protein (see Figure 3-5) and the Ga subunit of the trimeric G proteins. Both Ras and Ga are bound to the plasma membrane, function in cell signaling, and play a key role in cell proliferation and differentiation. Other members

▲ FIGURE 3-28 Switching mediated by Ca2+/calmodulin.

Calmodulin is a widely distributed cytosolic protein that contains four Ca2+-binding sites, one in each of its EF hands. Each EF hand has a helix-loop-helix motif. At cytosolic Ca2+ concentrations above about 5 X 10M, binding of Ca2+ to calmodulin changes the protein's conformation. The resulting Ca2+/calmodulin wraps around exposed helices of various target proteins, thereby altering their activity.

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