Allosteric regulation
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In biochemistry, allosteric regulation is the regulation of an enzyme or protein by binding an effector molecule at the protein's allosteric site (that is, a site other than the protein's active site). Effectors that enhance the protein's activity are referred to as allosteric activators, while those that decrease the protein's activation are called allosteric inhibitors. The term allostery comes from the Greek allos, "other", and stereos, "shape", referring to the regulatory site of an allosteric protein being separate from its active site.
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Models of allosteric regulation
Most allosteric effects can be explained by either the concerted (MWC) model put forth by Monod, Wyman, and Changeux, or by the sequential model described by Koshland, Nemethy, and Filmer. Both postulate that enzyme subunits exist in one of two conformations, tensed (T) or relaxed (R), and that relaxed subunits bind substrate more readily than those in the tense state. The two models differ most in their assumptions about subunit interaction.
Concerted model
The concerted model of allostery, also referred to as the symmetry model or MWC model, postulates that enzyme subunits are connected in such a way that a conformational change in one subunit is necessarily conferred to all other subunits. Thus all subunits must exist in the same conformation. The model further holds that in the absence of any ligand (substrate or otherwise), the equilibrium favors the T state over the R state. To summarize:
- all subunits must exist in the same conformation
- equilibrium favors the T state over the R state
The binding of substrate to one subunit causes all other subunits to assume the R state, thereby enhancing their affinity for substrate.
Sequential model
The sequential model of allosteric regulation holds that subunits are not connected in such a way that a conformational change in one induces a similar change in the others. Thus all enzyme subunits do not need to exist in the same conformation. Moreover, the sequential model dictates that molecules of substrate bind via an induced fit protocol. Namely, when a subunit randomly collides with a molecule of substrate, the active site essentially forms a glove around its substrate. While such an induced fit converts a subunit from the tensed to relaxed state, it does not propagate the conformational change to adjacent subunits. Instead, substrate binding at one subunit only slightly alters the structure of other subunits so that their binding sites are more receptive to substrate. To summarize:
- subunits need not exist in the same conformation
- molecules of substrate bind via induced fit protocol
- conformational changes are not propagated to all subunits
- substrate binding causes increased substrate affinity in adjacent subunits
Allosteric activation
Allosteric activation, such as the binding of oxygen molecules to hemoglobin, occurs when the binding of one ligand enhances the attraction between substrate molecules and other binding sites. With respect to hemoglobin, oxygen is effectively both the substrate and the effector. The allosteric, or "other," site is the active site of an adjoining protein subunit. The binding of oxygen to one subunit induces a conformational change in that subunit that interacts with the remaining active sites to enhance their oxygen affinity.
Allosteric inhibition
Allosteric inhibition occurs when the binding of one ligand decreases the affinity for substrate at other active sites. For example, when 2,3-BPG binds to a allosteric site on hemoglobin, the affinity for oxygen of all subunits decreases.
Types of effectors
Many allosteric proteins are regulated by their substrate; such a substrate is considered a homotropic allosteric modulator, and is typically an activator. Non-substrate regulatory molecules are called heterotropic allosteric modulators and can either be activators or inhibitors.
Some allosteric proteins can be regulated by their substrates and by other molecules as well. Such proteins are capable of both homotropic and heterotropic interactions.
