Too much of a good thing: regulated depletion of c-di-AMP in the bacterial cytoplasm - PubMed (original) (raw)

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Too much of a good thing: regulated depletion of c-di-AMP in the bacterial cytoplasm

TuAnh Ngoc Huynh et al. Curr Opin Microbiol. 2016 Apr.

Abstract

Bacteria that synthesize c-di-AMP also encode several mechanisms for controlling c-di-AMP levels within the cytoplasm. One major class of phosphodiesterases comprises GdpP and DhhP homologs, which degrade c-di-AMP into the linear molecule 5'-pApA or AMP by the DHH-DHHA1 domain. The other major class comprises PgpH homologs, which degrade c-di-AMP by the HD domain. Both GdpP and PgpH harbor sensory domains, likely to regulate c-di-AMP hydrolysis activity in response to signal input. As another possible mechanism for controlling cytoplasmic c-di-AMP levels, bacteria also secrete c-di-AMP via multidrug resistance transporters, as demonstrated for Listeria monocytogenes. Mutants that accumulate high c-di-AMP levels, by deletion of phosphodiesterases or multidrug resistance transporters, exhibit aberrant physiology, growth defects, and attenuated virulence in infection.

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Figures

Figure 1

Figure 1

Protein components of c-di-AMP depletion in the bacterial cytoplasm. PgpH and GdpP have sensory domains for integration of environmental and intracellular signals into enzymatic hydrolysis of c-di-AMP. DhhP (not shown) has a DHH-DHHA1 catalytic domain, but without accessory domains. Both PgpH and GdpP activities are inhibited by ppGpp. Heme-bound GdpP is activated by nitric oxide. Expression of MDRs is regulated by transcriptional factors of the MarR and TetR families. Small molecules such as bile acids influence DNA-binding activity of the TetR-like repressor BrtA and lead to transcriptional induction of MDRs. Enhanced MDR expression results in elevated secretion of bile acids and c-di-AMP.

Figure 2

Figure 2

Structural and sequence comparison of GdpP and DhhP catalytic domains. A – Crystal structure of the M. smegmatis DhhP (MSMEG_2630, PDB ID: 4LS9), also characterized as an NrnA oligoribonuclease. A metal ion is shown as a blue ball. A structural model of the GdpP DHH-DHHA1 domain, generated by the Phyre2 server, shows essentially the same fold, and is well aligned with NrnA. B and C – Comparison of conserved amino acids within the putative substrate recognition surface of the DHHA1 domain (top) and the metal binding site within the DHH domain (bottom). Similarly conserved residues are shown in magenta. GdpP also exhibits an additional conserved patch, shown in red, predicted for c-di-AMP binding by the Swissdock server. D - Sequence logos illustrating conserved residues of the GdpP DHH domain (top row) and DHHA1 domain (second and third rows), with conserved residues predicted for c-di-AMP binding labeled by a red bar. Residue 9 corresponds to Ile-341 in the B. subtilis GdpP sequence, residue 242 corresponds to Ile-574. E – Similar to D, but for DhhP homologs.

Figure 3

Figure 3

A- The c-di-AMP binding pocket in the HD domain active site of PgpH. His and Asp residues coordinate two metal ions (orange spheres). The phosphate of c-di-AMP coordinates these metal ions and hydrolysis occurs via a nucleophilic water molecule (red sphere) that is bridging between the metal ions. B- HD-domain catalytic mechanism for the phosphodiesterase reaction. Activated hydroxide group from the bridging water attacks the scissile phosphorous atom, with a 3’-hydroxyl as the leaving group, generating the linear product 5’-pApA. DHH-DHHA1 domains likely exhibit bi-nuclear active sites with a similar catalytic mechanism.

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References

    1. Corrigan RM, Grundling A. Cyclic di-AMP: another second messenger enters the fray. Nat Rev Microbiol. 2013;11:513–524. - PubMed
    1. Rao F, See RY, Zhang D, Toh DC, Ji Q, Liang ZX. YybT is a signaling protein that contains a cyclic dinucleotide phosphodiesterase domain and a GGDEF domain with ATPase activity. J Biol Chem. 2010;285:473–482. ** Of outstanding interest: The first and most extensive biochemical analysis of GdpP phosphodiesterase
    1. Ye M, Zhang JJ, Fang X, Lawlis GB, Troxell B, Zhou Y, Gomelsky M, Lou Y, Yang XF. DhhP, a c-di-AMP phosphodiesterase of Borrelia burgdorferi, is essential for cell growth and virulence. Infect Immun. 2014 * Of special interest: A demonstration that toxic c-di-AMP levels prevent bacterial growth and confer pleotropic phenotypes
    1. Uemura Y, Nakagawa N, Wakamatsu T, Kim K, Montelione GT, Hunt JF, Kuramitsu S, Masui R. Crystal structure of the ligand-binding form of nanoRNase from Bacteroides fragilis, a member of the DHH/DHHA1 phosphoesterase family of proteins. FEBS Lett. 2013;587:2669–2674. - PMC - PubMed
    1. Srivastav R, Kumar D, Grover A, Singh A, Manjasetty BA, Sharma R, Taneja B. Unique subunit packing in mycobacterial nanoRNase leads to alternate substrate recognitions in DHH phosphodiesterases. Nucleic Acids Res. 2014;42:7894–7910. - PMC - PubMed

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