Molecular Mechanism and Evolution of Guanylate Kinase Regulation by (p)ppGpp
The nucleotide (p)ppGpp mediates bacterial stress responses, but its targets and underlying mechanisms of action vary among bacterial species and remain incompletely understood. In this paper, we characterize the molecular interaction between (p)ppGpp and guanylate kinase (GMK), revealing the importance of this interaction in adaptation to starvation. Combining structural and kinetic analyses, we show that (p)ppGpp binds the GMK active site and competitively inhibits the enzyme. The (p)ppGpp-GMK interaction prevents the conversion of GMP to GDP, resulting in GMP accumulation upon amino acid downshift. Abolishing this interaction leads to excess (p)ppGpp and defective adaptation to amino acid starvation. A survey of GMKs from phylogenetically diverse bacteria shows that the (p)ppGpp-GMK interaction is conserved in members of Firmicutes, Actinobacteria, and Deinococcus-Thermus, but not in Proteobacteria, where (p)ppGpp regulates RNA polymerase (RNAP). Finally, we propose that GMK is an ancestral (p)ppGpp target and RNAP evolved more recently as a direct target in Proteobacteria.
- Research Organization:
- Univ. of Wisconsin, Madison, WI (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC)
- Grant/Contract Number:
- AC02-06CH11357
- OSTI ID:
- 1238689
- Alternate ID(s):
- OSTI ID: 1233992; OSTI ID: 1344483
- Journal Information:
- Molecular Cell, Journal Name: Molecular Cell Vol. 57 Journal Issue: 4; ISSN 1097-2765
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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