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Modelling intracellular competition for calcium: kinetic and thermodynamic control of different molecular modes of signal decoding.

ABSTRACT: Frequently, a common chemical entity triggers opposite cellular processes, which implies that the components of signalling networks must detect signals not only through their chemical natures, but also through their dynamic properties. To gain insights on the mechanisms of discrimination of the dynamic properties of cellular signals, we developed a computational stochastic model and investigated how three calcium ion (Ca(2+))-dependent enzymes (adenylyl cyclase (AC), phosphodiesterase 1 (PDE1), and calcineurin (CaN)) differentially detect Ca(2+) transients in a hippocampal dendritic spine. The balance among AC, PDE1 and CaN might determine the occurrence of opposite Ca(2+)-induced forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD). CaN is essential for LTD. AC and PDE1 regulate, indirectly, protein kinase A, which counteracts CaN during LTP. Stimulations of AC, PDE1 and CaN with artificial and physiological Ca(2+) signals demonstrated that AC and CaN have Ca(2+) requirements modulated dynamically by different properties of the signals used to stimulate them, because their interactions with Ca(2+) often occur under kinetic control. Contrarily, PDE1 responds to the immediate amplitude of different Ca(2+) transients and usually with the same Ca(2+) requirements observed under steady state. Therefore, AC, PDE1 and CaN decode different dynamic properties of Ca(2+) signals.

SUBMITTER: Antunes G

PROVIDER: S-EPMC4817061 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Modelling intracellular competition for calcium: kinetic and thermodynamic control of different molecular modes of signal decoding.

Antunes Gabriela G Roque Antonio C AC Simoes de Souza Fabio M FM

Scientific reports 20160401

Frequently, a common chemical entity triggers opposite cellular processes, which implies that the components of signalling networks must detect signals not only through their chemical natures, but also through their dynamic properties. To gain insights on the mechanisms of discrimination of the dynamic properties of cellular signals, we developed a computational stochastic model and investigated how three calcium ion (Ca(2+))-dependent enzymes (adenylyl cyclase (AC), phosphodiesterase 1 (PDE1), ...[more]

PMID: 27033299

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Project description:BackgroundThe importance of understanding the detailed mechanism of cysteine biosynthesis in bacteria is underscored by the fact that cysteine is the only sulfur donor for all cellular components containing reduced sulfur. O-acetylserine sulfhydrylase (OASS) catalyzes this crucial last step in the cysteine biosynthesis and has been recognized as an important gene for the survival and virulence of pathogenic bacteria. Structural and kinetic studies have contributed to the understanding of mechanistic aspects of OASS, but details of ligand recognition features of OASS are not available. In the absence of any detailed study on the energetics of ligand binding, we have studied the thermodynamics of OASS from Salmonella typhimurium (StOASS), Haemophilus influenzae (HiOASS), and Mycobacterium tuberculosis (MtOASS) binding to their substrate O-acetylserine (OAS), substrate analogue (methionine), and product (cysteine).ResultsLigand binding properties of three OASS enzymes are studied under defined solution conditions. Both substrate and product binding is an exothermic reaction, but their thermodynamic signatures are very different. Cysteine binding to OASS shows that both enthalpy and entropy contribute significantly to the binding free energy at all temperatures (10-30°C) examined. The analyses of interaction between OASS with OAS (substrate) or methionine (substrate analogue) revealed a completely different mode of binding. Binding of both OAS and methionine to OASS is dominated by a favorable entropy change, with minor contribution from enthalpy change (?H(St-Met) = -1.5 ± 0.1 kJ/mol; T?S(St-Met) = 8.2 kJ/mol) at 20°C. Our salt dependent ligand binding studies indicate that methionine binding affinity is more sensitive to [NaCl] as compared to cysteine affinity.ConclusionsWe show that OASS from three different pathogenic bacteria bind substrate and product through two different mechanisms. Results indicate that predominantly entropy driven methionine binding is not mediated through classical hydrophobic binding, instead, may involve desolvation of the polar active site. We speculate that OASS in general, may exhibit two different binding mechanisms for recognizing substrates and products.

Dataset Information

Modelling intracellular competition for calcium: kinetic and thermodynamic control of different molecular modes of signal decoding.

Publications

Modelling intracellular competition for calcium: kinetic and thermodynamic control of different molecular modes of signal decoding.

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