Abstract:
:The nucleotide (p)ppGpp mediates bacterial stress responses, but its targets and underlying mechanisms of action vary among bacterial species and remain incompletely understood. Here, 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). We propose that GMK is an ancestral (p)ppGpp target and RNAP evolved more recently as a direct target in Proteobacteria.
journal_name
Mol Celljournal_title
Molecular cellauthors
Liu K,Myers AR,Pisithkul T,Claas KR,Satyshur KA,Amador-Noguez D,Keck JL,Wang JDdoi
10.1016/j.molcel.2014.12.037subject
Has Abstractpub_date
2015-02-19 00:00:00pages
735-749issue
4eissn
1097-2765issn
1097-4164pii
S1097-2765(14)01015-6journal_volume
57pub_type
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