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.

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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.
    Structure 08/2015; 23(9). DOI:10.1016/j.str.2015.06.027 · 5.62 Impact Factor
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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.
    Biology and Philosophy 08/2015; DOI:10.1007/s10539-015-9497-8 · 1.19 Impact Factor
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    • "Many reviews and research papers have been written on the allosteric effect; the vast majority of these focus on allostery on the protein level (e.g., Cui and Karplus, 2008; del Sol et al., 2009; Endres et al., 2011; Goodey and Benkovic, 2008; Kenakin and Miller, 2010; Kenakin, 2009; Kuriyan and Eisenberg, 2007; Leitner, 2008; Ma et al., 2011; Tsai et al., 2009; Tzeng and Kalodimos, 2011; Whitley and Lee, 2009; Wrabl et al., 2011; Zhuravlev and Papoian, 2010; Zocchi, 2009). However, the fundamental importance of allostery is not in the functional effects on the protein itself but, rather, on the cell (Good et al., 2009; Good et al., 2011) and on the organism as a whole. "
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    ABSTRACT: Allostery is largely associated with conformational and functional transitions in individual proteins. This concept can be extended to consider the impact of conformational perturbations on cellular function and disease states. Here, we clarify the concept of allostery and how it controls physiological activities. We focus on the challenging questions of how allostery can both cause disease and contribute to development of new therapeutics. We aim to increase the awareness of the linkage between disease symptoms on the cellular level and specific aberrant allosteric actions on the molecular level and to emphasize the potential of allosteric drugs in innovative therapies.
    Cell 04/2013; 153(2):293-305. DOI:10.1016/j.cell.2013.03.034 · 32.24 Impact Factor
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