Is allostery a fuzzy concept?

TL;DR

This review discusses how the concept of allostery in proteins is ambiguous due to multiple definitions and unclear criteria for assigning reaction mechanisms.

Contribution

The paper clarifies criteria for assigning reaction mechanisms to allosteric proteins and emphasizes the need for structural analysis.

Findings

Allostery is used in multiple ways in literature, including regulation by heterotropic ligands and cooperativity in ligand binding.

Proteins considered allosteric may follow various mechanisms beyond the two-state model, such as ligand-induced fit or dissociation-association.

Reaction mechanism assignment is often imprecise without sufficient experimental evidence.

Abstract

Allostery is an important property of biological macromolecules which regulates diverse biological functions such as catalysis, signal transduction, transport, and molecular recognition. However, the concept was expressed using two different definitions by J. Monod and, over time, more have been added by different authors, making it fuzzy. Here, we reviewed the different meanings of allostery in the current literature and found that it has been used to indicate that the function of a protein is regulated by heterotropic ligands, and/or that the binding of ligands and substrates presents homotropic positive or negative cooperativity, whatever the hypothesized or demonstrated reaction mechanism might be. Thus, proteins defined to be allosteric include not only those that obey the two‐state concerted model, but also those that obey different reaction mechanisms such as ligand‐induced fit, possibly coupled to sequential structure changes, and ligand‐linked dissociation‐association. Since each reaction mechanism requires its own mathematical description and is defined by it, there are many possible ‘allosteries’. This lack of clarity is made even fuzzier by the fact that the reaction mechanism is often assigned imprecisely and/or implicitly in the absence of the necessary experimental evidence. In this review, we examine a list of proteins that have been defined to be allosteric and attempt to assign a reaction mechanism to as many as possible.

Assigning a reaction mechanism to allosteric proteins can be difficult. It is also unclear how many reaction mechanisms qualify as allosteric and the criteria used for assigning such mechanisms. Here, we define these criteria, apply them to a list of allosteric proteins, and suggest that reaction mechanism assignment should be considered preliminary until the structural analysis is carried out.

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