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TitleInhibition of the Staphylococcus aureus c-di-AMP cyclase DacA by direct interaction with the phosphoglucosamine mutase GlmM.
Journal, issue, pagesPLoS Pathog, Vol. 15, Issue 1, Page e1007537, Year 2019
Publish dateJan 22, 2019
AuthorsTommaso Tosi / Fumiya Hoshiga / Charlotte Millership / Rahul Singh / Charles Eldrid / Delphine Patin / Dominique Mengin-Lecreulx / Konstantinos Thalassinos / Paul Freemont / Angelika Gründling /
PubMed Abstractc-di-AMP is an important second messenger molecule that plays a pivotal role in regulating fundamental cellular processes, including osmotic and cell wall homeostasis in many Gram-positive organisms. ...c-di-AMP is an important second messenger molecule that plays a pivotal role in regulating fundamental cellular processes, including osmotic and cell wall homeostasis in many Gram-positive organisms. In the opportunistic human pathogen Staphylococcus aureus, c-di-AMP is produced by the membrane-anchored DacA enzyme. Inactivation of this enzyme leads to a growth arrest under standard laboratory growth conditions and a re-sensitization of methicillin-resistant S. aureus (MRSA) strains to ß-lactam antibiotics. The gene coding for DacA is part of the conserved three-gene dacA/ybbR/glmM operon that also encodes the proposed DacA regulator YbbR and the essential phosphoglucosamine mutase GlmM, which is required for the production of glucosamine-1-phosphate, an early intermediate of peptidoglycan synthesis. These three proteins are thought to form a complex in vivo and, in this manner, help to fine-tune the cellular c-di-AMP levels. To further characterize this important regulatory complex, we conducted a comprehensive structural and functional analysis of the S. aureus DacA and GlmM enzymes by determining the structures of the S. aureus GlmM enzyme and the catalytic domain of DacA. Both proteins were found to be dimers in solution as well as in the crystal structures. Further site-directed mutagenesis, structural and enzymatic studies showed that multiple DacA dimers need to interact for enzymatic activity. We also show that DacA and GlmM form a stable complex in vitro and that S. aureus GlmM, but not Escherichia coli or Pseudomonas aeruginosa GlmM, acts as a strong inhibitor of DacA function without the requirement of any additional cellular factor. Based on Small Angle X-ray Scattering (SAXS) data, a model of the complex revealed that GlmM likely inhibits DacA by masking the active site of the cyclase and preventing higher oligomer formation. Together these results provide an important mechanistic insight into how c-di-AMP production can be regulated in the cell.
External linksPLoS Pathog / PubMed:30668586 / PubMed Central
MethodsSAS (X-ray synchrotron) / X-ray diffraction
Resolution1.7 - 3 Å
Structure data

SASDE78:
Solution structure of the diadenylate cyclase/phosphoglucosamine mutase (DacA/GlmM) complex from Staphylococcus aureus
Method: SAXS/SANS

SASDE88:
Solution structure of phosphoglucosamine mutase (GlmM) from Staphylococcus aureus
Method: SAXS/SANS

SASDE98:
Solution structure of Diadenylate cyclase (DacA) from Staphylococcus aureus
Method: SAXS/SANS

PDB-6gyw:
Crystal structure of DacA from Staphylococcus aureus
Method: X-RAY DIFFRACTION / Resolution: 1.7 Å

PDB-6gyx:
Crystal structure of DacA from Staphylococcus aureus in complex with ApCpp
Method: X-RAY DIFFRACTION / Resolution: 2.6 Å

PDB-6gyy:
Crystal structure of DacA from Staphylococcus aureus, N166C/T172C double mutant
Method: X-RAY DIFFRACTION / Resolution: 2.77 Å

PDB-6gyz:
Crystal structure of GlmM from Staphylococcus aureus
Method: X-RAY DIFFRACTION / Resolution: 3.0 Å

Chemicals

ChemComp-HOH:
WATER

ChemComp-APC:
DIPHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER / AMP-CPP, energy-carrying molecule analogue*YM

ChemComp-MN:
Unknown entry

Source
  • Staphylococcus aureus (strain usa300) (bacteria)
  • staphylococcus aureus (bacteria)
KeywordsTRANSFERASE / c-di-AMP / diadenylate cyclase / ApCpp / protein engineering / ISOMERASE / cell wall / phosphoglucosamine mutase / peptidoglycan

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