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: 6.79). 09/2009; 17(8):1042-50. DOI: 10.1016/j.str.2009.06.008
Source: PubMed

ABSTRACT 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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    • "However, it is well established that native state of proteins is better represented by an ensemble of different conformers in dynamical equilibrium (Tsai et al. 1999). The concept of conformational ensemble is a central key to explain essential properties of proteins such as (Boehr et al. 2006; del Sol et al. 2009; Hilser 2010; Ma and Nussinov 2010), enzyme and antibody promiscuity (James et al. 2003), signal transduction (Smock and Gierasch 2009), and protein– protein recognition (Yogurtcu et al. 2008). In this work, we have studied the influence of conformational diversity on protein evolutionary rate. "
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    ABSTRACT: Native state of proteins is better represented by an ensemble of conformers in equilibrium than by only one structure. The extension of structural differences between conformers characterizes the conformational diversity of the protein. In this study we found a negative correlation between conformational diversity and protein evolutionary rate. Conformational diversity was expressed as the maximum RMSD between the available conformers in CoDNaS database. Evolutionary rate estimations were calculated using 16 different species compared to human sharing at least 700 orthologous proteins with known conformational diversity extension. The negative correlation found is independent of the protein expression level and comparable in magnitude and sign with the correlation between gene expression level and evolutionary rate. Our findings suggest that the structural constraints underlying protein dynamism, essential for protein function, could modulate protein divergence.
    Molecular Biology and Evolution 04/2013; 30(7). DOI:10.1093/molbev/mst065 · 14.31 Impact Factor
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    • "Eventually, the extended MWC model that includes negative cooperativity [6] was introduced. Numerous studies have since been performed of the MWC and KNF models at different levels of coarse-graining, such as analysis of local perturbations [7] [8], using normal modes [9] for quantifying energetic and entropic contributions to allostery [10] [11] [12] and associated conformational changes [13] [14], and implementing network description of allosteric signaling [15] [16] [17] [18] [19]. At some point, original restrictions of the MWC and KNF models on considering only oligomeric structures were dropped, and allostery is currently analyzed in proteins with a wide range of sizes, shapes [20], and functions [15,21–25]. "
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    ABSTRACT: We overview here our recent work on the thermodynamic view of allosteric regulation and communication. Starting from the geometry-based prediction of regulatory binding sites in a static structure, we move on to exploring a connection between ligand binding and the intrinsic dynamics of the protein molecule. We describe here two recently introduced measures, binding leverage and leverage coupling, which allow one to analyze the molecular basis of allosteric regulation. We discuss the advantages of these measures and show that they work universally in proteins of different sizes, oligomeric states, and functions. We also point to the problems that have to be solved before completing an atomic level description of allostery, and briefly discuss ideas for computational design of allosteric drugs.
    Biochimica et Biophysica Acta 01/2013; 1834(5). DOI:10.1016/j.bbapap.2013.01.024 · 4.66 Impact Factor
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    • "Because endogenous ligand binding is regulated by the cellular environment, they act when the biological state of the cell needs their action; that is, they preserve the natural cellular rhythm. To understand these effects and what can happen in the presence of a disease-causing mutation, we need to consider the origin of the communication pathways and how they spread (del Sol et al., 2009). Proteins are flexible and information flows through dynamic changes in the distribution of their ensembles. "
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    ABSTRACT: Mutations, even if not directly in the ligand binding sites of proteins, can lead to disease. In cell surface receptors, this can happen if they uncouple conformational changes that take place upon agonist (or antagonist) binding to the extracellular domain and the intracellular response. Uncoupling can take place by disrupting a major allosteric propagation pathway between the extra- and intracellular domains. Here I provide a mechanistic explanation: I first describe how propagation takes place; second, what can happen in the presence of a disease-related mutation which is distant from the binding site; and finally, how drugs may overcome this disruption and rescue function. The mutations in the glycine receptor α1 subunit (α1R271Q/L) which cause the neuromotor disorder hyperekplexia are on example of such allosteric mutations. In this issue of the BJP, Shan et al. show that normal function was restored to these mutant receptors by substitution of the segment which contained the mutated position, by a homologous one. An allosteric drug could mimic the effects of such substitution. Within this framework, I highlight the advantages of allosteric drugs and the challenges in their design.
    British Journal of Pharmacology 11/2011; 165(7):2110-2. DOI:10.1111/j.1476-5381.2011.01793.x · 4.99 Impact Factor
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