Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Hemoglobin Binds Oxygen Cooperatively

Hemoglobin must bind oxygen efficiently in the lungs, where the pO₂ is about 13.3 kPa, and release oxygen in the tissues, where the pO₂ is about 4 kPa. Myoglobin, or any protein that binds oxygen with a hyperbolic binding curve, would be ill-suited to this function, for the reason illustrated in Figure 5–12. A protein that bound O₂ with high affinity would bind it efficiently in the lungs but would not release much of it in the tissues. If the protein bound oxygen with a sufficiently low affinity to release it in the tissues, it would not pick up much oxy gen in the lungs. Hemoglobin solves the problem by undergoing a transition from a low-affinity state (the T state) to a high-affinity state (the R state) as more O₂ molecules are bound. As a result, hemoglobin has a hybrid S shaped, or sigmoid, binding curve for oxygen (Fig. 5–12). A single-subunit protein with a single ligand binding site cannot produce a sigmoid binding curve— even if binding elicits a conformational change— because each molecule of ligand binds independently and cannot affect the binding of another molecule. In contrast, O₂ binding to individual subunits of hemoglobin can alter the affinity for O₂ in adjacent subunits. The first molecule of O₂ that interacts with deoxyhe moglobin binds weakly, because it binds to a subunit in the T state. Its binding, however, leads to conformational changes that are communicated to adjacent subunits making it easier for additional molecules of O₂ to bind. In effect, the T → R transition occurs more readily in the second subunit once O₂ is bound to the first subunit. The last (fourth) O₂ molecule binds to a heme in a subunit that is already in the R state, and hence it binds with much higher affinity than the first molecule.

An allosteric protein is one in which the binding of a ligand to one site affects the binding properties of another site on the same protein. The term “allosteric” derives from the Greek allos “other” and stereos “solid” or “shape.” Allosteric proteins are those having “other shapes” or conformations, induced by the binding of ligands referred to as modulators. The conformational changes induced by the modulator(s) interconvert more-active and less-active forms of the protein. The modulators for allosteric proteins may be either inhibitors or activators. When the normal ligand and modulator are identical, the interaction is termed homotropic. 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 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 entire binding site were highly stable, then few structural changes could occur in this site or be propagated to other parts of the protein when a ligand binds. As is the case with myoglobin, ligands other than oxygen can bind to hemoglobin. An important example is carbon monoxide which binds to hemoglobin about 250 times better than does oxygen. Human exposure to CO can have tragic consequences (Box 5–1).

FIGURE 5–11 Changes in conformation near heme on O₂ binding to deoxyhemoglobin. (Derived from PDB ID 1HGA and 1BBB.) The shift in the position of the F helix when heme binds O₂ is thought to be one of the adjustments that triggers the T → R transition.

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 tis sues 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).

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 con formation 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.

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