Allostery: An Overview of Its History, Concepts, Methods, and Applications

Liu, Jin; Nussinov, Ruth

doi:10.1371/journal.pcbi.1004966

Cited by 240 publications

(213 citation statements)

References 23 publications

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“…(A) The per‐residue free energy difference ∆ g i between the apo‐ and FBP‐bound MD simulations were calculated according to the method presented in , giving the difference in the amount of configurational work exerted on each residue i due to allosteric ligand binding. The numbers and blue bars indicate the HLH , FBP‐binding pocket and a third site encompassing residues 86–97 that are energetically stabilised by FBP binding (negative on the ∆ g i scale). Conversely, residues in the B‐domain yield a significant increase of configurational work (positive on the ∆ g i scale) as a result of allosteric communication between sites.…”

Section: Resultsmentioning

confidence: 99%

An engineered photoswitchable mammalian pyruvate kinase

et al. 2017

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Changes in allosteric regulation of glycolytic enzymes have been linked to metabolic reprogramming involved in cancer. Remarkably, allosteric mechanisms control enzyme function at significantly shorter time‐scales compared to the long‐term effects of metabolic reprogramming on cell proliferation. It remains unclear if and how the speed and reversibility afforded by rapid allosteric control of metabolic enzymes is important for cell proliferation. Tools that allow specific, dynamic modulation of enzymatic activities in mammalian cells would help address this question. Towards this goal, we have used molecular dynamics simulations to guide the design of mPKM2 internal light/oxygen/voltage‐sensitive domain 2 (LOV2) fusion at position D24 (PiL[D24]), an engineered pyruvate kinase M2 (PKM2) variant that harbours an insertion of the light‐sensing LOV2 domain from Avena Sativa within a region implicated in allosteric regulation by fructose 1,6‐bisphosphate (FBP). The LOV2 photoreaction is preserved in the PiL[D24] chimera and causes secondary structure changes that are associated with a 30% decrease in the K m of the enzyme for phosphoenolpyruvate resulting in increased pyruvate kinase activity after light exposure. Importantly, this change in activity is reversible upon light withdrawal. Expression of PiL[D24] in cells leads to light‐induced increase in labelling of pyruvate from glucose. PiL[D24] therefore could provide a means to modulate cellular glucose metabolism in a remote manner and paves the way for studying the importance of rapid allosteric phenomena in the regulation of metabolism and enzyme control.

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Section: Resultsmentioning

confidence: 99%

An engineered photoswitchable mammalian pyruvate kinase

et al. 2017

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“…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: 99%

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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“…Allostery (Tsai et al, 2009;Tsai and Nussinov, 2014;Liu and Nussinov, 2016) is a mode of long-distance communication between distal sites in proteins, in which the energy released as a consequence of conformational or dynamic changes at one site can travel along specific pathways within the protein structure to other sites, changing their conformational or dynamic properties (Liu and Nussinov, 2017). Computational methods directly relating protein structural dynamics to information exchange between functional sites have also been devised (Lenaerts et al, 2008).…”

Section: Rri As Allosteric Interactionsmentioning

confidence: 99%

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Guidolin

Marcoli

Tortorella

et al. 2018

Reviews in the Neurosciences

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Abstract:The proposal of receptor-receptor interactions (RRIs) in the early 1980s broadened the view on the role of G protein-coupled receptors (GPCR) in the dynamics of the intercellular communication. RRIs, indeed, allow GPCR to operate not only as monomers but also as receptor complexes, in which the integration of the incoming signals depends on the number, spatial arrangement, and order of activation of the protomers forming the complex. The main biochemical mechanisms controlling the functional interplay of GPCR in the receptor complexes are direct allosteric interactions between protomer domains. The formation of these macromolecular assemblies has several physiologic implications in terms of the modulation of the signaling pathways and interaction with other membrane proteins. It also impacts on the emerging field of connectomics, as it contributes to set and tune the synaptic strength. Furthermore, recent evidence suggests that the transfer of GPCR and GPCR complexes between cells via the exosome pathway could enable the target cells to recognize/decode transmitters and/or modulators for which they did not express the pertinent receptors. Thus, this process may also open the possibility of a new type of redeployment of neural circuits. The fundamental aspects of GPCR complex formation and function are the focus of the present review article.

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Allostery: An Overview of Its History, Concepts, Methods, and Applications

Cited by 240 publications

References 23 publications

An engineered photoswitchable mammalian pyruvate kinase

An engineered photoswitchable mammalian pyruvate kinase

Allosteric Regulation of Mammalian Pantothenate Kinase

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

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