Allosteric communication in mammalian muscle aldolase

Sygusch, J.; Beaudry, D.

doi:10.1042/bj3270717

Cited by 14 publications

(7 citation statements)

References 27 publications

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“…At this stage we were left with two proteins, aldolase and HSP90, and arbitrarily chose aldolase. For human aldolase there is a known functional coupling between two aldolase regions[ 73 ] and several CSCs ( Fig. 13A ) overlapped with them.…”

Section: Resultsmentioning

confidence: 99%

“…To check whether our CSCs overlapped with allosteric couplings, and to which extent, we explored the literature and the Allosteric Database[ 72 ] (ASD, version 2.0). The information retrieved shows that experimental data were available for nine proteins: aldolase[ 73 , 74 ], annexin V[ 75 – 78 ], transferrin[ 79 – 82 ], retinol-binding protein[ 83 – 86 ] (RBP), purine nucleoside phosphorylase[ 87 , 88 ] (PNP), heat shock protein HSP90[ 89 ], cyclophilin A[ 90 – 92 ], interleukin-1alpha[ 93 , 94 ], and Awd nucleotide diphosphate kinase[ 95 ]. When comparing functional site (FS)/allosteric site (AS) annotations with our CSC data, we found several cases where the regions linked by both couplings overlapped: one cavity in the CSC would involve a number of FS residues and the other cavity would involve a number of AS residues (see below).…”

Section: Methodsmentioning

confidence: 99%

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Molecular Dynamics Study of Naturally Existing Cavity Couplings in Proteins

et al. 2015

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Couplings between protein sub-structures are a common property of protein dynamics. Some of these couplings are especially interesting since they relate to function and its regulation. In this article we have studied the case of cavity couplings because cavities can host functional sites, allosteric sites, and are the locus of interactions with the cell milieu. We have divided this problem into two parts. In the first part, we have explored the presence of cavity couplings in the natural dynamics of 75 proteins, using 20 ns molecular dynamics simulations. For each of these proteins, we have obtained two trajectories around their native state. After applying a stringent filtering procedure, we found significant cavity correlations in 60% of the proteins. We analyze and discuss the structure origins of these correlations, including neighbourhood, cavity distance, etc. In the second part of our study, we have used longer simulations (≥100ns) from the MoDEL project, to obtain a broader view of cavity couplings, particularly about their dependence on time. Using moving window computations we explored the fluctuations of cavity couplings along time, finding that these couplings could fluctuate substantially during the trajectory, reaching in several cases correlations above 0.25/0.5. In summary, we describe the structural origin and the variations with time of cavity couplings. We complete our work with a brief discussion of the biological implications of these results.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Molecular Dynamics Study of Naturally Existing Cavity Couplings in Proteins

et al. 2015

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“…Modification of Cys-72 and Cys-338 either by their crosslinking 33 or by oxidized glutathione inhibits catalytic activity 34 through long range communication with the active site ~25Å distant. Long range inhibition of dynamical events during catalysis requisite for ALDOA activity by UM0112176, as was shown for oxidized glutathione inactivation of ALDOA 34 , is consistent with its inhibition kinetics. Intriguingly, Lys-293 has been shown to promote γ-actin interaction with ALDOA as K293A mutation abrogates the binding 26 .…”

Section: Introductionmentioning

confidence: 99%

Targeting a moonlighting function of aldolase induces apoptosis in cancer cells

et al. 2019

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Muscle fructose-1,6-bisphosphate aldolase (ALDOA) is among the most abundant glycolytic enzymes in all cancer cells. Here, we show that the enzyme plays a previously unknown and critical role in a cancer cell survival. Simultaneous inhibition of ALDOA activity and interaction with F-actin cytoskeleton using ALDOA slow-binding inhibitor UM0112176 leads to a rapid cofilin-dependent loss of F-actin stress fibers which is associated with elevated ROS production, inhibition of ATP synthesis, increase in calcium levels, caspase activation and arrested cellular proliferation. These effects can be reproduced by silencing of ALDOA. The mechanism of pharmacological action is, however, independent of the catalytic function of the enzyme, specific to cancer cells, and is most deleterious to cells undergoing the epithelial–mesenchymal transition, a process facilitating cancer cell invasion. Our results demonstrate that the overabundance of ALDOA in cancer cells is associated with its moonlighting rather than catalytic functions. This may have significant implications for development of novel broad-based anti-cancer therapies.

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“…It appears that the quaternary structure not only stabilizes the molecule but also constrains the configuration that each subunit adopts and thereby promotes cooperative interactions in an active tetramer. Sygusch and Beaudry (28) have recently demonstrated cooperativity in the rabbit A isozyme. This may be a general phenomenon relating to all the multimeric class I aldolases.…”

Section: Figmentioning

confidence: 99%

Expression, Purification, and Characterization of Natural Mutants of Human Aldolase B

Rellos¹,

Sygusch²,

Cox³

2000

Journal of Biological Chemistry

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Fructaldolases (EC 4.1.2.13) are ancient enzymes of glycolysis that catalyze the reversible cleavage of phosphofructose esters into cognate triose (phosphates). Three vertebrate isozymes of Class I aldolase have arisen by gene duplication and display distinct activity profiles with fructose 1,6-bisphosphate and with fructose 1-phosphate. We describe the biochemical and biophysical characterization of seven natural human aldolase B variants, identified in patients suffering from hereditary fructose intolerance and expressed as recombinant proteins in E. coli, from which they were purified to homogeneity. The mutant aldolases were all missense variants and could be classified into two principal groups: catalytic mutants, with retained tetrameric structure but altered kinetic properties (W147R, R303W, and A337V), and structural mutants, in which the homotetramers readily dissociate into subunits with greatly impaired enzymatic activity (A149P, A174D, L256P, and N334K). Investigation of these two classes of mutant enzyme suggests that the integrity of the quaternary structure of aldolase B is critical for maintaining its full catalytic function.

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Allosteric communication in mammalian muscle aldolase

Cited by 14 publications

References 27 publications

Molecular Dynamics Study of Naturally Existing Cavity Couplings in Proteins

Molecular Dynamics Study of Naturally Existing Cavity Couplings in Proteins

Targeting a moonlighting function of aldolase induces apoptosis in cancer cells

Expression, Purification, and Characterization of Natural Mutants of Human Aldolase B

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