Allostery and the Monod-Wyman-Changeux Model After 50 Years

Changeux, Jean‐Pierre

doi:10.1146/annurev-biophys-050511-102222

Cited by 339 publications

(332 citation statements)

References 154 publications

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“…The MWC model put forward about 50 y ago (2) has been applied to a wide range of systems (18,19), but the debate between proponents of the concerted (MWC) and sequential (KNF) models has continued. Distinguishing between these allosteric mechanisms is of fundamental interest and is also important because of their functional implications.…”

Section: Resultsmentioning

confidence: 99%

Allosteric mechanisms can be distinguished using structural mass spectrometry

Dyachenko

Gruber

Shimon³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

133

151

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The activity of many proteins, including metabolic enzymes, molecular machines, and ion channels, is often regulated by conformational changes that are induced or stabilized by ligand binding. In cases of multimeric proteins, such allosteric regulation has often been described by the concerted Monod-Wyman-Changeux and sequential Koshland-Némethy-Filmer classic models of cooperativity. Despite the important functional implications of the mechanism of cooperativity, it has been impossible in many cases to distinguish between these various allosteric models using ensemble measurements of ligand binding in bulk protein solutions. Here, we demonstrate that structural MS offers a way to break this impasse by providing the full distribution of ligand-bound states of a protein complex. Given this distribution, it is possible to determine all the binding constants of a ligand to a highly multimeric cooperative system, and thereby infer its allosteric mechanism. Our approach to the dissection of allosteric mechanisms relies on advances in MSwhich provide the required resolution of ligand-bound states-and in data analysis. We validated our approach using the well-characterized Escherichia coli chaperone GroEL, a double-heptameric ring containing 14 ATP binding sites, which has become a paradigm for molecular machines. The values of the 14 binding constants of ATP to GroEL were determined, and the ATP-loading pathway of the chaperone was characterized. The methodology and analyses presented here are directly applicable to numerous other cooperative systems and are therefore expected to promote further research on allosteric systems.chaperonins | Hill coefficient M ultimeric proteins are often subject to allosteric regulation that is achieved by conformational changes induced or stabilized by ligand binding (1). Such allosteric regulation has been described by two classic models: (i) the Monod-WymanChangeux (MWC) model (2), in which conformational changes occur in a concerted manner and symmetry is conserved, and (ii) the Koshland-Némethy-Filmer (KNF) model (3), in which conformational changes take place in a sequential manner and symmetry is broken. In addition, it has been proposed more recently that conformational changes can take place in a probabilistic manner (4). The allosteric control of protein activity is frequently manifested in sigmoidal plots of initial reaction velocity or fractional saturation as a function of the ligand (substrate) concentration that indicates positive cooperativity in ligand binding. It has been impossible, however, to extract any mechanistic insights from these plots (5) because they only show how an average property of the ensemble (e.g., fractional saturation) changes with ligand concentration and do not reveal how the distribution of ligand-bound states changes with ligand concentration. Thus, for example, it is not possible to determine from such sigmoidal plots whether an allosteric transition takes place in a concerted MWC-like fashion (2) or via a sequential KNF-like mechanism (3). T...

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Section: Resultsmentioning

confidence: 99%

Allosteric mechanisms can be distinguished using structural mass spectrometry

Dyachenko

Gruber

Shimon³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

133

151

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“…Although our biochemical and structural analyses provide an accurate description of the key conformations pertinent to PANK3 regulation in vivo, it is not a complete biochemical description of all possible PANK3 states. Whereas the allosteric behavior of PANK3 is most easily understood in light of the Monod, Wyman, and Changeux model for cooperativity that posits that the ligandfree protein exists in two structurally coupled conformational states (25,26), we have no specific structural data that directly support the existence of two distinct ligand-free states. Instead, the ligand-free state may be more dynamic with one or more intermediate state(s) where localized unfolding may exist (27)(28)(29).…”

Section: Discussionmentioning

confidence: 98%

Allosteric Regulation of Mammalian Pantothenate Kinase

Subramanian

Yun²,

Yao

et al. 2016

Journal of Biological Chemistry

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Pantothenate kinase catalyzes the key regulatory step in CoA biosynthesis in bacteria and mammals (1-3). In mammals, there are four distinct kinases that exhibit tissue-specific expression as follows: PANK1␣ and PANK1␤ are splice variants of the PANK1 gene, and PANK2 and PANK3 are encoded by the PANK2 and PANK3 genes, respectively (4, 5). The kinase isoforms possess almost identical catalytic cores but differ in their amino termini that direct the enzymes to different subcellular compartments (6). Isoform 1␣ is targeted to the nucleus, whereas isoform 1␤ is associated with endosomes in humans and mice. Isoform 2 of mice is cytosolic, but the PANK2 gene in humans encodes a protein with both nuclear localization and mitochondrial targeting sequences. Isoform 3 is cytosolic in both species. All pantothenate kinases operate by a compulsory ordered mechanism with ATP⅐Mg 2ϩ as the leading substrate followed by pantothenate ( Fig. 1) (7). The principal mechanism for controlling mammalian pantothenate kinase activity is through feedback inhibition by acetyl-CoA, and the isoforms differ in their sensitivity to this regulator ( Fig. 1) (4, 8, 9). The 1␣ and 1␤ isoforms are least sensitive to inhibition, whereas isoforms 2 and 3 are more potently inhibited by acetyl-CoA. Acetyl-CoA inhibition is competitive with ATP⅐Mg 2ϩ , but acetyl-CoA binds far more tightly than ATP (10). Acyl-carnitines antagonize the inhibition of pantothenate kinases by acetyl-CoA (8).The importance of pantothenate kinase to mammalian physiology is highlighted by the phenotypes of knock-out mice and their connection to human disease. Isoform 1 is most highly expressed in the liver, and Pank1 Ϫ/Ϫ mice have lower total hepatic CoA and exhibit fatty acid ␤-oxidation and glucose homeostasis defects in the fasted state (11). In addition, Pank1 Ϫ/Ϫ Lep Ϫ/Ϫ mice have dramatically lower blood glucose and insulin levels compared with their diabetic Lep Ϫ/Ϫ counterparts, which highlights the connection between isoform 1 and glucose homeostasis (12). Consistent with this, an association between polymorphisms in the PANK1 gene and insulin levels was uncovered in a cohort of individuals in Finland (13). It has also been shown that the severe neurodegenerative disease pantothenate kinase-associated neurodegeneration arises from mutations in the human PANK2 gene (14). Unfortunately, Pank2 Ϫ/Ϫ mice do not recapitulate the pantothenate kinaseassociated neurodegeneration disease phenotype (15,16), and this may be due either to differences in the levels of isoform expression in mouse and human brains or to the fact that human PANK2 accumulates in the intra-membrane space in mitochondria, whereas mouse isoform 2 is cytosolic (9). Finally, Pank1 Ϫ/Ϫ Pank2 Ϫ/Ϫ double knock-out mice are unable to metabolize fats and ketones resulting in early postnatal death (16), and Pank1 Ϫ/Ϫ Pank3 Ϫ/Ϫ and Pank2 Ϫ/Ϫ Pank3 Ϫ/Ϫ double knock-out mice are both embryonic lethal. A chemical knockout of all pantothenate kinases in adult mice resulted in an 80% reduction in hepatic CoA levels a...

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“…For decades, two models accounting for receptor activation have been widely debated, postulating that either (i) a receptor exists in an equilibrium of a few discrete states, independently of ligand structure and occupancy, and that these states might be differentially stabilized by ligands (conformational selection model), or that (ii) a conformational transition between static states only occurs after a ligand-induced change in shape of the protein (induced fit model) 1 . A validation of one of these models would have important consequences on our understanding of the molecular bases of ligand efficacy.…”

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confidence: 99%

Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy

et al. 2014

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Efficient cell-to-cell communication relies on the accurate signalling of cell surface receptors. Understanding the molecular bases of their activation requires the characterization of the dynamic equilibrium between active and resting states. Here, we monitor, using single-molecule Förster resonance energy transfer, the kinetics of the reorientation of the extracellular ligand-binding domain of the metabotropic glutamate receptor (mGluR), a class C G-protein-coupled receptor. We demonstrate that most receptors oscillate between a resting-and an active-conformation on a sub-millisecond timescale. Interestingly, we demonstrate that differences in agonist efficacies stem from differing abilities to shift the conformational equilibrium towards the fully active state, rather than from the stabilization of alternative static conformations, which further highlights the dynamic nature of mGluRs and revises our understanding of receptor activation and allosteric modulation.

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Allostery and the Monod-Wyman-Changeux Model After 50 Years

Cited by 339 publications

References 154 publications

Allosteric mechanisms can be distinguished using structural mass spectrometry

Allosteric mechanisms can be distinguished using structural mass spectrometry

Allosteric Regulation of Mammalian Pantothenate Kinase

Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy

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