The Origin of Allosteric Functional Modulation: Multiple Pre-existing Pathways

Bioinformatics Research Unit, Research and Development Division, Fujirebio Inc., Hachioji-shi, Tokyo, Japan.
Structure (Impact Factor: 5.62). 09/2009; 17(8):1042-50. DOI: 10.1016/j.str.2009.06.008
Source: PubMed


Although allostery draws increasing attention, not much is known about allosteric mechanisms. Here we argue that in all proteins, allosteric signals transmit through multiple, pre-existing pathways; which pathways dominate depend on protein topologies, specific binding events, covalent modifications, and cellular (environmental) conditions. Further, perturbation events at any site on the protein surface (or in the interior) will not create new pathways but only shift the pre-existing ensemble of pathways. Drugs binding at different sites or mutational events in disease shift the ensemble toward the same conformations; however, the relative populations of the different states will change. Consequently the observed functional, conformational, and dynamic effects will be different. This is the origin of allosteric functional modulation in dynamic proteins: allostery does not necessarily need to invoke conformational rearrangements to control protein activity and pre-existing pathways are always defaulted to during allostery regardless of the stimulant and perturbation site in the protein.

    • "However, the ligand does not elicit a conformational change, but it provides the Gibbs energy required for the redistribution of the populations and shifts the equilibrium towards particular conformational states within a pre-existing conformational equilibrium. This scenario is consistent with the broad definition of allostery: allosterism is the modulation of the protein conformational equilibrium by ligand binding [5] [6] [7] [8] [9]. This definition can be reconciled with the traditional, more restrictive , definition of allostery, that is, the cooperative phenomenon in which the binding of a given ligand to a macromolecule is influenced by the binding of another ligand. "
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    ABSTRACT: Background: Conformational changes coupled to ligand binding constitute the structural and energetics basis underlying cooperativity, allostery and, in general, protein regulation. These conformational rearrangements are associated to heat capacity changes. ITC is a unique technique for studying binding interactions because of the simultaneous determination of the binding affinity and enthalpy, and for providing the best estimates of binding heat capacity changes. Scope of review: Still controversial issues in ligand binding are the discrimination between the "conformational selection model" and the "induced fit model", and whether or not conformational changes lead to temperature dependent apparent binding heat capacities. The assessment of conformational changes associated to ligand binding by ITC is discussed. In addition, the "conformational selection" and "induced fit" models are reconciled, and discussed within the context of intrinsically (partially) unstructured proteins. Major conclusions: Conformational equilibrium is a major contribution to binding heat capacity changes. A simple model may explain both conformational selection and induced fit scenarios. A temperature-independent binding heat capacity does not necessarily indicate absence of conformational changes upon ligand binding. ITC provides information on the energetics of conformational changes associated to ligand binding (and other possible additional coupled equilibria). General significance: Preferential ligand binding to certain protein states leads to an equilibrium shifts that is reflected in the coupling between ligand binding and additional equilibria. This represents the structural/energetic basis of the widespread dependence of ligand binding parameters on temperature, as well as pH, ionic strength and the concentration of other chemical species. This article is part of a Special Issue entitled Microcalorimetry in the BioSciences - Principles and Applications, edited by Fadi Bou-Abdallah.
    No preview · Article · Oct 2015 · Biochimica et Biophysica Acta
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    • "Communication between functional sites is central to protein regulation. In most cases, the pathways through which the signal propagates are poorly characterized (Goodey and Benkovic, 2008; del Sol et al., 2009; Lu et al., 2014c; Fetics et al., 2015). Here, we show that protection of pT308 level by ATP depends on formation of a finely tuned network of interactions within the G loop and helix aC. "
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    ABSTRACT: Kinases use ATP to phosphorylate substrates; recent findings underscore the additional regulatory roles of ATP. Here, we propose a mechanism for allosteric regulation of Akt1 kinase phosphorylation by ATP. Our 4.7-μs molecular dynamics simulations of Akt1 and its mutants in the ATP/ADP bound/unbound states revealed that ATP occupancy of the ATP-binding site stabilizes the closed conformation, allosterically protecting pT308 by restraining phosphatase access and key interconnected residues on the ATP→pT308 allosteric pathway. Following ATP→ADP hydrolysis, pT308 is exposed and readily dephosphorylated. Site-directed mutagenesis validated these predictions and indicated that the mutations do not impair PDK1 and PP2A phosphatase recruitment. We further probed the function of residues around pT308 at the atomic level, and predicted and experimentally confirmed that Akt1(H194R/R273H) double mutant rescues pathology-related Akt1(R273H). Analysis of classical Akt homologs suggests that this mechanism can provide a general model of allosteric kinase regulation by ATP; as such, it offers a potential avenue for allosteric drug discovery. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Aug 2015 · Structure
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    • "14 Allosterism (Monod et al. 1963; 1965; Koshland et al. 1966) concerns the change in the structure and functioning of a protein due to the interaction with an effector molecule in a site different from the active one (primary functional activity). The nature and variety of allosteric mechanisms has been widely discussed in the literature (see Morange 2012; and Cornish-Bowden 2014 for a review of the debate) and, still,new theoretical models have beenrecently formulated (Del Sol, et al. 2009; Motlagh et al. 2014). The important aspect of allosteric proteins is that, having two distinct sites, they can respond to effectors and change their activity accordingly. "
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    ABSTRACT: Biological regulation is what allows an organism to handle the effects of a perturbation, modulating its own constitutive dynamics in response to particular changes in internal and external conditions. With the central focus of analysis on the case of minimal living systems, we argue that regulation consists in a specific form of second-order control, exerted over the core (constitutive) regime of production and maintenance of the components that actually put together the organism. The main argument is that regulation requires a distinctive architecture of functional relationships, and specifically the action of a dedicated subsystem whose activity is dynamically decoupled from that of the constitutive regime. We distinguish between two major ways in which control mechanisms contribute to the maintenance of a biological organisation in response to internal and external perturbations: dynamic stability and regulation. Based on this distinction an explicit definition and a set of organisational requirements for regulation are provided, and thoroughly illustrated through the examples of bacterial chemotaxis and the lac-operon. The analysis enables us to mark out the differences between regulation and closely related concepts such as feedback, robustness and homeostasis.
    Full-text · Article · Aug 2015 · Biology and Philosophy
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