Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps
Sensor histidine kinases (SHKs) are an integral component of the molecular machinery that permits bacteria to adapt to widely changing environmental conditions. CpxA, an extensively studied SHK, is a multidomain homodimeric protein with each subunit consisting of a periplasmic sensor domain, a trans...
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2018
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0006291X_v498_n2_p305_Marsico http://hdl.handle.net/20.500.12110/paper_0006291X_v498_n2_p305_Marsico |
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paper:paper_0006291X_v498_n2_p305_Marsico2023-06-08T14:30:23Z Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps Coarse grain CpxA Histidine kinase QM/MM Two component system histidine protein CpxA protein histidine kinase unclassified drug adenosine triphosphate CpxA protein, E coli Escherichia coli protein histidine protein kinase Article autophosphorylation catalysis computer simulation enzyme activation enzyme conformation enzyme mechanism enzyme phosphorylation molecular dynamics priority journal chemistry metabolism molecular dynamics pH phosphorylation protein conformation protein domain Adenosine Triphosphate Escherichia coli Proteins Histidine Hydrogen-Ion Concentration Molecular Dynamics Simulation Phosphorylation Protein Conformation Protein Domains Protein Kinases Sensor histidine kinases (SHKs) are an integral component of the molecular machinery that permits bacteria to adapt to widely changing environmental conditions. CpxA, an extensively studied SHK, is a multidomain homodimeric protein with each subunit consisting of a periplasmic sensor domain, a transmembrane domain, a signal-transducing HAMP domain, a dimerization and histidine phospho-acceptor sub-domain (DHp) and a catalytic and ATP-binding subdomain (CA). The key activation event involves the rearrangement of the HAMP-DHp helical core and translation of the CA towards the acceptor histidine, which presumably results in an autokinase-competent complex. In the present work we integrate coarse-grained, all-atom, and hybrid QM-MM computer simulations to probe the large-scale conformational reorganization that takes place from the inactive to the autokinase-competent state (conformational step), and evaluate its relation to the autokinase reaction itself (chemical step). Our results highlight a tight coupling between conformational and chemical steps, underscoring the advantage of CA walking along the DHp core, to favor a reactive tautomeric state of the phospho-acceptor histidine. The results not only represent an example of multiscale modelling, but also show how protein dynamics can promote catalysis. © 2017 Elsevier Inc. 2018 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0006291X_v498_n2_p305_Marsico http://hdl.handle.net/20.500.12110/paper_0006291X_v498_n2_p305_Marsico |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Coarse grain CpxA Histidine kinase QM/MM Two component system histidine protein CpxA protein histidine kinase unclassified drug adenosine triphosphate CpxA protein, E coli Escherichia coli protein histidine protein kinase Article autophosphorylation catalysis computer simulation enzyme activation enzyme conformation enzyme mechanism enzyme phosphorylation molecular dynamics priority journal chemistry metabolism molecular dynamics pH phosphorylation protein conformation protein domain Adenosine Triphosphate Escherichia coli Proteins Histidine Hydrogen-Ion Concentration Molecular Dynamics Simulation Phosphorylation Protein Conformation Protein Domains Protein Kinases |
| spellingShingle |
Coarse grain CpxA Histidine kinase QM/MM Two component system histidine protein CpxA protein histidine kinase unclassified drug adenosine triphosphate CpxA protein, E coli Escherichia coli protein histidine protein kinase Article autophosphorylation catalysis computer simulation enzyme activation enzyme conformation enzyme mechanism enzyme phosphorylation molecular dynamics priority journal chemistry metabolism molecular dynamics pH phosphorylation protein conformation protein domain Adenosine Triphosphate Escherichia coli Proteins Histidine Hydrogen-Ion Concentration Molecular Dynamics Simulation Phosphorylation Protein Conformation Protein Domains Protein Kinases Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps |
| topic_facet |
Coarse grain CpxA Histidine kinase QM/MM Two component system histidine protein CpxA protein histidine kinase unclassified drug adenosine triphosphate CpxA protein, E coli Escherichia coli protein histidine protein kinase Article autophosphorylation catalysis computer simulation enzyme activation enzyme conformation enzyme mechanism enzyme phosphorylation molecular dynamics priority journal chemistry metabolism molecular dynamics pH phosphorylation protein conformation protein domain Adenosine Triphosphate Escherichia coli Proteins Histidine Hydrogen-Ion Concentration Molecular Dynamics Simulation Phosphorylation Protein Conformation Protein Domains Protein Kinases |
| description |
Sensor histidine kinases (SHKs) are an integral component of the molecular machinery that permits bacteria to adapt to widely changing environmental conditions. CpxA, an extensively studied SHK, is a multidomain homodimeric protein with each subunit consisting of a periplasmic sensor domain, a transmembrane domain, a signal-transducing HAMP domain, a dimerization and histidine phospho-acceptor sub-domain (DHp) and a catalytic and ATP-binding subdomain (CA). The key activation event involves the rearrangement of the HAMP-DHp helical core and translation of the CA towards the acceptor histidine, which presumably results in an autokinase-competent complex. In the present work we integrate coarse-grained, all-atom, and hybrid QM-MM computer simulations to probe the large-scale conformational reorganization that takes place from the inactive to the autokinase-competent state (conformational step), and evaluate its relation to the autokinase reaction itself (chemical step). Our results highlight a tight coupling between conformational and chemical steps, underscoring the advantage of CA walking along the DHp core, to favor a reactive tautomeric state of the phospho-acceptor histidine. The results not only represent an example of multiscale modelling, but also show how protein dynamics can promote catalysis. © 2017 Elsevier Inc. |
| title |
Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps |
| title_short |
Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps |
| title_full |
Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps |
| title_fullStr |
Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps |
| title_full_unstemmed |
Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps |
| title_sort |
multiscale approach to the activation and phosphotransfer mechanism of cpxa histidine kinase reveals a tight coupling between conformational and chemical steps |
| publishDate |
2018 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0006291X_v498_n2_p305_Marsico http://hdl.handle.net/20.500.12110/paper_0006291X_v498_n2_p305_Marsico |
| _version_ |
1768545262927609856 |