Inherent Regulation of EAL Domain-catalyzed Hydrolysis of Second Messenger Cyclic di-GMP

The universal second messenger cyclic di-GMP (cdG) is involved in the regulation of a diverse range of cellular processes in bacteria. The intracellular concentration of the dinucleotide is determined by the opposing actions of diguanylate cyclases and cdG-specific phosphodiesterases (PDEs). Whereas...

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Veröffentlicht in:The Journal of biological chemistry 2014-03, Vol.289 (10), p.6978-6990
Hauptverfasser: Sundriyal, Amit, Massa, Claudia, Samoray, Dietrich, Zehender, Fabian, Sharpe, Timothy, Jenal, Urs, Schirmer, Tilman
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container_end_page 6990
container_issue 10
container_start_page 6978
container_title The Journal of biological chemistry
container_volume 289
creator Sundriyal, Amit
Massa, Claudia
Samoray, Dietrich
Zehender, Fabian
Sharpe, Timothy
Jenal, Urs
Schirmer, Tilman
description The universal second messenger cyclic di-GMP (cdG) is involved in the regulation of a diverse range of cellular processes in bacteria. The intracellular concentration of the dinucleotide is determined by the opposing actions of diguanylate cyclases and cdG-specific phosphodiesterases (PDEs). Whereas most PDEs have accessory domains that are involved in the regulation of their activity, the regulatory mechanism of this class of enzymes has remained unclear. Here, we use biophysical and functional analyses to show that the isolated EAL domain of a PDE from Escherichia coli (YahA) is in a fast thermodynamic monomer-dimer equilibrium, and that the domain is active only in its dimeric state. Furthermore, our data indicate thermodynamic coupling between substrate binding and EAL dimerization with the dimerization affinity being increased about 100-fold upon substrate binding. Crystal structures of the YahA-EAL domain determined under various conditions (apo, Mg2+, cdG·Ca2+ complex) confirm structural coupling between the dimer interface and the catalytic center. The built-in regulatory properties of the EAL domain probably facilitate its modular, functional combination with the diverse repertoire of accessory domains. Background: The bacterial second messenger cyclic di-GMP (c-di-GMP) is degraded by EAL phosphodiesterases. Results: The isolated EAL domain is active only as a homodimer. Substrate binding is coupled with EAL dimerization. Conclusion: Activity of many full-length EAL phosphodiesterases may be regulated by catalytic domain dimerization. Significance: A generic mechanism for the regulation of a central node of c-di-GMP signaling is provided.
doi_str_mv 10.1074/jbc.M113.516195
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The intracellular concentration of the dinucleotide is determined by the opposing actions of diguanylate cyclases and cdG-specific phosphodiesterases (PDEs). Whereas most PDEs have accessory domains that are involved in the regulation of their activity, the regulatory mechanism of this class of enzymes has remained unclear. Here, we use biophysical and functional analyses to show that the isolated EAL domain of a PDE from Escherichia coli (YahA) is in a fast thermodynamic monomer-dimer equilibrium, and that the domain is active only in its dimeric state. Furthermore, our data indicate thermodynamic coupling between substrate binding and EAL dimerization with the dimerization affinity being increased about 100-fold upon substrate binding. Crystal structures of the YahA-EAL domain determined under various conditions (apo, Mg2+, cdG·Ca2+ complex) confirm structural coupling between the dimer interface and the catalytic center. The built-in regulatory properties of the EAL domain probably facilitate its modular, functional combination with the diverse repertoire of accessory domains. Background: The bacterial second messenger cyclic di-GMP (c-di-GMP) is degraded by EAL phosphodiesterases. Results: The isolated EAL domain is active only as a homodimer. Substrate binding is coupled with EAL dimerization. Conclusion: Activity of many full-length EAL phosphodiesterases may be regulated by catalytic domain dimerization. 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The built-in regulatory properties of the EAL domain probably facilitate its modular, functional combination with the diverse repertoire of accessory domains. Background: The bacterial second messenger cyclic di-GMP (c-di-GMP) is degraded by EAL phosphodiesterases. Results: The isolated EAL domain is active only as a homodimer. Substrate binding is coupled with EAL dimerization. Conclusion: Activity of many full-length EAL phosphodiesterases may be regulated by catalytic domain dimerization. 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subjects 3',5'-Cyclic-GMP Phosphodiesterases - chemistry
3',5'-Cyclic-GMP Phosphodiesterases - genetics
3',5'-Cyclic-GMP Phosphodiesterases - metabolism
Allosteric Regulation
Amino Acid Sequence
Bacterial Signal Transduction
c-di-GMP Signaling
Catalysis
Catalytic Domain
Chromatography
Crystal Structure
Crystallography, X-Ray
Cyclic GMP - analogs & derivatives
Cyclic GMP - chemistry
Cyclic GMP - metabolism
Escherichia coli Proteins - chemistry
Escherichia coli Proteins - genetics
Escherichia coli Proteins - metabolism
Hydrolysis
Molecular Biophysics
Molecular Sequence Data
Phosphodiesterases
Protein Multimerization
Protein Structure, Tertiary
Second Messenger
Second Messenger Systems
title Inherent Regulation of EAL Domain-catalyzed Hydrolysis of Second Messenger Cyclic di-GMP
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