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:2021:10.1016/j.jbc.2021.101317,
author = {Pathania, M and Tosi, T and Millership, C and Hoshiga, F and Morgan, RML and Freemont, PS and Grundling, A},
doi = {10.1016/j.jbc.2021.101317},
journal = {Journal of Biological Chemistry},
pages = {1--15},
title = {Structural basis for the inhibition of the Bacillus subtilis c-di-AMP cyclase CdaA by the phosphoglucomutase GlmM},
url = {http://dx.doi.org/10.1016/j.jbc.2021.101317},
volume = {297},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Cyclic-di-adenosine monophosphate (c-di-AMP) is an important nucleotide signaling molecule that plays a key role in osmotic regulation in bacteria. c-di-AMP is produced from two molecules of ATP by proteins containing a diadenylate cyclase (DAC) domain. In Bacillus subtilis, the main c-di-AMP cyclase, CdaA, is a membrane-linked cyclase with an N-terminal transmembrane domain followed by the cytoplasmic DAC domain. As both high and low levels of c-di-AMP have a negative impact on bacterial growth, the cellular levels of this signaling nucleotide are tightly regulated. Here we investigated how the activity of the B. subtilis CdaA is regulated by the phosphoglucomutase GlmM, which has been shown to interact with the c-di-AMP cyclase. Using the soluble B. subtilis CdaACD catalytic domain and purified full-length GlmM or the GlmMF369 variant lacking the C-terminal flexible domain 4, we show 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 CdaACD and GlmM homodimers and of the CdaACD:GlmMF369 complex. In the complex structure, a CdaACD dimer is bound to a GlmMF369 dimer in such a manner that GlmM blocks the oligomerization of CdaACD and formation of active head-to-head cyclase oligomers, thus suggesting a mechanism by which GlmM acts as a cyclase inhibitor. As the amino acids at the CdaACD:GlmM interphase are conserved, we propose that the observed mechanism of inhibition of CdaA by GlmM may also be conserved among Firmicutes.
AU  - Pathania,M
AU  - Tosi,T
AU  - Millership,C
AU  - Hoshiga,F
AU  - Morgan,RML
AU  - Freemont,PS
AU  - Grundling,A
DO  - 10.1016/j.jbc.2021.101317
EP  - 15
PY  - 2021///
SN  - 0021-9258
SP  - 1
TI  - Structural basis for the inhibition of the Bacillus subtilis c-di-AMP cyclase CdaA by the phosphoglucomutase GlmM
T2  - Journal of Biological Chemistry
UR  - http://dx.doi.org/10.1016/j.jbc.2021.101317
UR  - https://www.sciencedirect.com/science/article/pii/S0021925821011236?via%3Dihub
UR  - http://hdl.handle.net/10044/1/92731
VL  - 297
ER  -
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