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FIGURE 5-12 A sigmoid (cooperative) binding curve. A sigmoid binding curve can be viewed as a hybrid curve reflecting a transition from a low-affinity to a high-affinity state. Cooperative binding, as manifested by a sigmoid binding curve, renders hemoglobin more sensitive to the small differences in O2 concentration between the tissues and the lungs, allowing hemoglobin to bind oxygen in the lungs (where pO2 is high) and release it in the tissues (where pO2 is low).

modulator are identical, the interaction is termed ho-motropic. When the modulator is a molecule other than the normal ligand the interaction is heterotropic. Some proteins have two or more modulators and therefore can have both homotropic and heterotropic interactions.

Cooperative binding of a ligand to a multimeric protein, such as we observe with the binding of O2 to hemoglobin, is a form of allosteric binding often observed in multimeric proteins. The binding of one ligand affects

FIGURE 5-13 Structural changes in a multisubunit protein undergoing cooperative binding to ligand. Structural stability is not uniform throughout a protein molecule. Shown here is a hypothetical dimeric protein, with regions of high (blue), medium (green), and low (red) stability. The ligand-binding sites are composed of both high- and low-stability segments, so affinity for ligand is relatively low. (a) In the absence of ligand, the red segments are quite flexible and take up a variety of conformations, few of which facilitate ligand binding. The green segments are most stable in the low-affinity state. (b) The binding of ligand to one subunit stabilizes a high-affinity conformation of the nearby red segment (now shown in green), inducing a conformational change in the rest of the polypeptide. This is a form of induced fit. The conformational change is transmitted to the other subunit through protein-protein interactions, such that a higher-affinity conformation of the binding site is stabilized in the other subunit. (c) A second ligand molecule can now bind to the second subunit, with a higher affinity than the binding of the first, giving rise to the observed positive cooperativity.

the affinities of any remaining unfilled binding sites, and O2 can be considered as both a ligand and an activating homotropic modulator. There is only one binding site for O2 on each subunit, so the allosteric effects giving rise to cooperativity are mediated by conformational changes transmitted from one subunit to another by subunit-subunit interactions. A sigmoid binding curve is diagnostic of cooperative binding. It permits a much more sensitive response to ligand concentration and is important to the function of many multisubunit proteins. The principle of allostery extends readily to regulatory enzymes, as we shall see in Chapter 6.

Cooperative conformational changes depend on variations in the structural stability of different parts of a protein, as described in Chapter 4. The binding sites of an allosteric protein typically consist of stable segments in proximity to relatively unstable segments, with the latter capable of frequent changes in conformation or disorganized motion (Fig. 5-13). When a ligand binds, the moving parts of the protein's binding site may be stabilized in a particular conformation, affecting the conformation of adjacent polypeptide subunits. If the

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