Structural basis of KdpD histidine kinase binding to the second messenger c-di-AMP
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved..
The KdpDE two-component system regulates potassium homeostasis and virulence in various bacterial species. The KdpD histidine kinases (HK) of this system contain a universal stress protein (USP) domain which binds to the second messenger cyclic-di-adenosine monophosphate (c-di-AMP) for regulating transcriptional output from this two-component system in Firmicutes such as Staphylococcus aureus. However, the structural basis of c-di-AMP specificity within the KdpD-USP domain is not well understood. Here, we resolved a 2.3 Å crystal structure of the S. aureus KdpD-USP domain (USPSa) complexed with c-di-AMP. Binding affinity analyses of USPSa mutants targeting the observed USPSa:c-di-AMP structural interface enabled the identification of the sequence residues that are required for c-di-AMP specificity. Based on the conservation of these residues in other Firmicutes, we identified the binding motif, (A/G/C)XSXSX2N(Y/F), which allowed us to predict c-di-AMP binding in other KdpD HKs. Furthermore, we found that the USPSa domain contains structural features distinct from the canonical standalone USPs that bind ATP as a preferred ligand. These features include inward-facing conformations of its β1-α1 and β4-α4 loops, a short α2 helix, the absence of a triphosphate-binding Walker A motif, and a unique dual phospho-ligand binding mode. It is therefore likely that USPSa-like domains in KdpD HKs represent a novel subfamily of the USPs.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2021 |
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Erschienen: |
2021 |
Enthalten in: |
Zur Gesamtaufnahme - volume:296 |
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Enthalten in: |
The Journal of biological chemistry - 296(2021) vom: 06. Jan., Seite 100771 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Dutta, Anirudha [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 31.08.2021 Date Revised 07.11.2023 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1016/j.jbc.2021.100771 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM325409927 |
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520 | |a Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved. | ||
520 | |a The KdpDE two-component system regulates potassium homeostasis and virulence in various bacterial species. The KdpD histidine kinases (HK) of this system contain a universal stress protein (USP) domain which binds to the second messenger cyclic-di-adenosine monophosphate (c-di-AMP) for regulating transcriptional output from this two-component system in Firmicutes such as Staphylococcus aureus. However, the structural basis of c-di-AMP specificity within the KdpD-USP domain is not well understood. Here, we resolved a 2.3 Å crystal structure of the S. aureus KdpD-USP domain (USPSa) complexed with c-di-AMP. Binding affinity analyses of USPSa mutants targeting the observed USPSa:c-di-AMP structural interface enabled the identification of the sequence residues that are required for c-di-AMP specificity. Based on the conservation of these residues in other Firmicutes, we identified the binding motif, (A/G/C)XSXSX2N(Y/F), which allowed us to predict c-di-AMP binding in other KdpD HKs. Furthermore, we found that the USPSa domain contains structural features distinct from the canonical standalone USPs that bind ATP as a preferred ligand. These features include inward-facing conformations of its β1-α1 and β4-α4 loops, a short α2 helix, the absence of a triphosphate-binding Walker A motif, and a unique dual phospho-ligand binding mode. It is therefore likely that USPSa-like domains in KdpD HKs represent a novel subfamily of the USPs | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a bacterial signal transduction | |
650 | 4 | |a c-di-AMP | |
650 | 4 | |a crystal structure | |
650 | 4 | |a histidine kinase | |
650 | 4 | |a methicillin-resistant Staphylococcus aureus | |
650 | 4 | |a osmoregulation | |
650 | 4 | |a second messenger | |
650 | 7 | |a Bacterial Proteins |2 NLM | |
650 | 7 | |a Cyclic AMP |2 NLM | |
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650 | 7 | |a Protein Kinases |2 NLM | |
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650 | 7 | |a EC 2.7.- |2 NLM | |
650 | 7 | |a Histidine Kinase |2 NLM | |
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700 | 1 | |a Batish, Mona |e verfasserin |4 aut | |
700 | 1 | |a Parashar, Vijay |e verfasserin |4 aut | |
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