Imperial College London
Alternate

Professor Angelika Gründling

Faculty of Medicine, Department of Infectious Disease

Professor of Molecular Microbiology
 
 
 
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Contact

 

+44 (0)20 7594 5256a.grundling Website

 
 
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Location

 

6.22Flowers buildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Pathania:2021:10.1101/2021.05.26.445777,
author = {Pathania, M and Tosi, T and Millership, C and Hoshiga, F and Morgan, R and Freemont, P and Gründling, A},
doi = {10.1101/2021.05.26.445777},
title = {Structural basis for the inhibition of the <i>Bacillus subtilis</i> c-di-AMP cyclase CdaA by the phosphoglucomutase GlmM},
url = {http://dx.doi.org/10.1101/2021.05.26.445777},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Cyclic-di-adenosine monophosphate (c-di-AMP) is an important nucleotide signalling molecule, which plays a key role in osmotic regulation in bacteria. Cellular c-di-AMP levels are tightly regulated, as both high and low levels have a negative impact on bacterial growth. Here, we investigated how the activity of the main Bacillus subtilis c-di-AMP cyclase CdaA is regulated by the phosphoglucomutase GlmM. c-di-AMP is produced from two molecules of ATP by proteins containing a deadenylate cyclase (DAC) domain. CdaA is a membrane-linked cyclase with an N-terminal transmembrane domain followed by the cytoplasmic DAC domain. Here we show, using the soluble catalytic B. subtilis CdaA CD domain and purified full-length GlmM or the GlmM F369 variant lacking the C-terminal flexible domain 4, that the cyclase and phosphoglucomutase form a stable complex in vitro and that GlmM is a potent cyclase inhibitor. We determined the crystal structure of the individual B. subtilis CdaA CD and GlmM proteins, both of which form dimers in the structures, and of the CdaA CD GlmM F369 complex. In the complex structure, a CdaA CD dimer is bound to a GlmM F369 dimer in such a manner that GlmM blocks the oligomerization of CdaA CD and formation of active head-to-head cyclase oligomers, thus providing molecular details on how GlmM acts as cyclase inhibitor. The function of a key amino acid residue in CdaA CD in complex formation was confirmed by mutagenesis analysis. As the amino acids at the CdaA CD GlmM interphase are conserved, we propose that the observed inhibition mechanism of CdaA by GlmM is conserved among Firmicutes.
AU  - Pathania,M
AU  - Tosi,T
AU  - Millership,C
AU  - Hoshiga,F
AU  - Morgan,R
AU  - Freemont,P
AU  - Gründling,A
DO  - 10.1101/2021.05.26.445777
PY  - 2021///
TI  - Structural basis for the inhibition of the <i>Bacillus subtilis</i> c-di-AMP cyclase CdaA by the phosphoglucomutase GlmM
UR  - http://dx.doi.org/10.1101/2021.05.26.445777
ER  -
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