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Review
. 2008 Apr 18;378(1):1-11.
doi: 10.1016/j.jmb.2008.02.034. Epub 2008 Feb 29.

Allostery: absence of a change in shape does not imply that allostery is not at play

Chung-Jung Tsai  1 , Antonio del Sol, Ruth Nussinov
Affiliations
Review

Allostery: absence of a change in shape does not imply that allostery is not at play

Chung-Jung Tsai et al. J Mol Biol. .

Abstract

Allostery is essential for controlled catalysis, signal transmission, receptor trafficking, turning genes on and off, and apoptosis. It governs the organism's response to environmental and metabolic cues, dictating transient partner interactions in the cellular network. Textbooks taught us that allostery is a change of shape at one site on the protein surface brought about by ligand binding to another. For several years, it has been broadly accepted that the change of shape is not induced; rather, it is observed simply because a larger protein population presents it. Current data indicate that while side chains can reorient and rewire, allostery may not even involve a change of (backbone) shape. Assuming that the enthalpy change does not reverse the free-energy change due to the change in entropy, entropy is mainly responsible for binding.

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Figures

Figure 1
Figure 1
A schematic drawing illustrating the allosteric effect. Here the allosteric effect is referred to as a change at one site (allosteric site) affecting the activity of another site (active site). In this drawing, the activity at both sites is depicted as a ligand binding event: an effector binding to the allosteric site and a substrate binding to the active site. The location of the two binding sites could be adjacent or distal (as shown in the drawing) to each other. The allosteric effect is said to show positive cooperativity if the effector binding increases the affinity for the substrate (favorable binding free energy). Conversely, if the effector binding lowers the substrate affinity, it exhibits negative cooperativity. The change at the allosteric site (an effector binding in the drawing) might, or might not, alter the conformation at the active site. Therefore, there are four combinations of allosteric effects in terms of positive/negative cooperativity versus with/without conformational changes. Here we illustrate only two of these cases in terms of the relative free energy change: positive allosteric regulation without conformational change in Figure 1A; and negative allosteric regulation with conformational change in Figure 1B. In positive allosteric regulation (Figure 1A), the event of the effector binding at the allosteric site (indicated as Allosteric regulation) switches it from an Off regulation state to an On regulation state. Note that the discrete On or Off regulation state in the Figure is highlighted in order to reflect the outcome of the cellular regulation functionality. For a general definition of the allosteric effect, the degree of change is always continuous either increasing or decreasing the affinity at the substrate site. The allosteric binding clearly shows that the previous unfavorable substrate binding for the Off state (indicated by a big cross) becomes favorable for the On state. In negative allosteric regulation (Figure 1B), an effector binding at the allosteric site (also indicated as an Allosteric regulation) switches it from an On regulation state to an Off regulation state. Here, the allosteric binding indicates that the previous favorable substrate binding for the On state becomes unfavorable (indicated by a big cross) for the Off state. The conformational change due to the effector binding is highlighted in pink color around the active site.
Figure 1
Figure 1
A schematic drawing illustrating the allosteric effect. Here the allosteric effect is referred to as a change at one site (allosteric site) affecting the activity of another site (active site). In this drawing, the activity at both sites is depicted as a ligand binding event: an effector binding to the allosteric site and a substrate binding to the active site. The location of the two binding sites could be adjacent or distal (as shown in the drawing) to each other. The allosteric effect is said to show positive cooperativity if the effector binding increases the affinity for the substrate (favorable binding free energy). Conversely, if the effector binding lowers the substrate affinity, it exhibits negative cooperativity. The change at the allosteric site (an effector binding in the drawing) might, or might not, alter the conformation at the active site. Therefore, there are four combinations of allosteric effects in terms of positive/negative cooperativity versus with/without conformational changes. Here we illustrate only two of these cases in terms of the relative free energy change: positive allosteric regulation without conformational change in Figure 1A; and negative allosteric regulation with conformational change in Figure 1B. In positive allosteric regulation (Figure 1A), the event of the effector binding at the allosteric site (indicated as Allosteric regulation) switches it from an Off regulation state to an On regulation state. Note that the discrete On or Off regulation state in the Figure is highlighted in order to reflect the outcome of the cellular regulation functionality. For a general definition of the allosteric effect, the degree of change is always continuous either increasing or decreasing the affinity at the substrate site. The allosteric binding clearly shows that the previous unfavorable substrate binding for the Off state (indicated by a big cross) becomes favorable for the On state. In negative allosteric regulation (Figure 1B), an effector binding at the allosteric site (also indicated as an Allosteric regulation) switches it from an On regulation state to an Off regulation state. Here, the allosteric binding indicates that the previous favorable substrate binding for the On state becomes unfavorable (indicated by a big cross) for the Off state. The conformational change due to the effector binding is highlighted in pink color around the active site.
Figure 2
Figure 2
A schematic drawing to illustrate both positive and negative allosteric effects via a non-additive entropic contribution. Since entropy involving solvent is excluded in this drawing, a binding event here is assumed to be accompanied by an entropy loss. The higher the bar with an indicated quantity, -TΔS (entropy in terms of free energy), the more unfavorable the relative entropy loss. The green bar -TΔSE reflects the entropy loss when an effector molecule binds to the allosteric site; the red bar -TΔSS represents the entropy loss when a substrate binds to the allosteric protein active site. If there is no allosteric effect at play, each individual binding is considered independent of the other. Hence, the entropy loss is additive as -T(ΔSE+ΔSS). In positive cooperative binding, the entropy loss of the first (effector) binding prepays most of the entropy loss that the second (substrate) binding has to pay. Hence the entropy loss -TΔSE+S is much less than the sum of the entropy loss of the individual binding events. While in negative cooperative binding, the first binding does not pay for the entropy loss due to the second binding and together they incur an extra substantial entropy loss. The resulting -TΔSE+S is much higher than -T(ΔSE+ΔSS).
Figure 3
Figure 3
Visualization of the overall conformational changes in allosteric proteins. Four pairs of known inactive and active allosteric protein structures from the Protein Data Bank are illustrated. In each pair, the protein backbone trace is represented by solid ribbon and the side-chains are drawn as thin lines. The effector molecule binding (or covalent modification) to the active allosteric protein is shown in space-fill (atom color codes are Carbon yellow, Nitrogen green, Oxygen red, Phosphorus light green, Sulfur pink, Magnesium cyan, and Iron blue). The ligand is located at the allosteric site. However, even if present in the PDB file of the inactive protein, it is not shown here for clarity. The superposition is based on matched residues with the distance between superimposed Cα atoms <= 2.0 Å. The scaffold of the matched residues is colored pink and light green, respectively for the inactive and active allosteric proteins. The conformational changes (unmatched residues) are highlighted in red and green, respectively for the inactive and active allosteric proteins. Here four pictures are illustrated as examples of conformational changes in allostery: (A) hemoglobin (PDB codes: 2hhb A and 1hho A); this case has been classified in the no-change category, (B) fixJ (1dbw A; 1d5w A): classified as subtle (C) arf6 (1e0s A; 1hfv A): classified minor, (D) purR (1dbq A; 1wet A): classified domain-movement.
Figure 3
Figure 3
Visualization of the overall conformational changes in allosteric proteins. Four pairs of known inactive and active allosteric protein structures from the Protein Data Bank are illustrated. In each pair, the protein backbone trace is represented by solid ribbon and the side-chains are drawn as thin lines. The effector molecule binding (or covalent modification) to the active allosteric protein is shown in space-fill (atom color codes are Carbon yellow, Nitrogen green, Oxygen red, Phosphorus light green, Sulfur pink, Magnesium cyan, and Iron blue). The ligand is located at the allosteric site. However, even if present in the PDB file of the inactive protein, it is not shown here for clarity. The superposition is based on matched residues with the distance between superimposed Cα atoms <= 2.0 Å. The scaffold of the matched residues is colored pink and light green, respectively for the inactive and active allosteric proteins. The conformational changes (unmatched residues) are highlighted in red and green, respectively for the inactive and active allosteric proteins. Here four pictures are illustrated as examples of conformational changes in allostery: (A) hemoglobin (PDB codes: 2hhb A and 1hho A); this case has been classified in the no-change category, (B) fixJ (1dbw A; 1d5w A): classified as subtle (C) arf6 (1e0s A; 1hfv A): classified minor, (D) purR (1dbq A; 1wet A): classified domain-movement.
Figure 3
Figure 3
Visualization of the overall conformational changes in allosteric proteins. Four pairs of known inactive and active allosteric protein structures from the Protein Data Bank are illustrated. In each pair, the protein backbone trace is represented by solid ribbon and the side-chains are drawn as thin lines. The effector molecule binding (or covalent modification) to the active allosteric protein is shown in space-fill (atom color codes are Carbon yellow, Nitrogen green, Oxygen red, Phosphorus light green, Sulfur pink, Magnesium cyan, and Iron blue). The ligand is located at the allosteric site. However, even if present in the PDB file of the inactive protein, it is not shown here for clarity. The superposition is based on matched residues with the distance between superimposed Cα atoms <= 2.0 Å. The scaffold of the matched residues is colored pink and light green, respectively for the inactive and active allosteric proteins. The conformational changes (unmatched residues) are highlighted in red and green, respectively for the inactive and active allosteric proteins. Here four pictures are illustrated as examples of conformational changes in allostery: (A) hemoglobin (PDB codes: 2hhb A and 1hho A); this case has been classified in the no-change category, (B) fixJ (1dbw A; 1d5w A): classified as subtle (C) arf6 (1e0s A; 1hfv A): classified minor, (D) purR (1dbq A; 1wet A): classified domain-movement.
Figure 3
Figure 3
Visualization of the overall conformational changes in allosteric proteins. Four pairs of known inactive and active allosteric protein structures from the Protein Data Bank are illustrated. In each pair, the protein backbone trace is represented by solid ribbon and the side-chains are drawn as thin lines. The effector molecule binding (or covalent modification) to the active allosteric protein is shown in space-fill (atom color codes are Carbon yellow, Nitrogen green, Oxygen red, Phosphorus light green, Sulfur pink, Magnesium cyan, and Iron blue). The ligand is located at the allosteric site. However, even if present in the PDB file of the inactive protein, it is not shown here for clarity. The superposition is based on matched residues with the distance between superimposed Cα atoms <= 2.0 Å. The scaffold of the matched residues is colored pink and light green, respectively for the inactive and active allosteric proteins. The conformational changes (unmatched residues) are highlighted in red and green, respectively for the inactive and active allosteric proteins. Here four pictures are illustrated as examples of conformational changes in allostery: (A) hemoglobin (PDB codes: 2hhb A and 1hho A); this case has been classified in the no-change category, (B) fixJ (1dbw A; 1d5w A): classified as subtle (C) arf6 (1e0s A; 1hfv A): classified minor, (D) purR (1dbq A; 1wet A): classified domain-movement.
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