ppGpp Coordinates Nucleotide and Amino-Acid Synthesis in E. coli During Starvation
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nihms-1649834.pdf
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Accepted version
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2.95 MB
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Author(s)
Wang, Boyuan
Grant, Robert A
Laub, Michael T
Date Issued
August 27, 2020
Journal
Molecular Cell
Publisher
Elsevier BV
Citation
Boyuan Wang, Robert A. Grant, Michael T. Laub,
ppGpp Coordinates Nucleotide and Amino-Acid Synthesis in E. coli During Starvation, Molecular Cell, Volume 80, Issue 1, 2020 © 2020 Elsevier Inc.
Version
Author's final manuscript
Abstract
(p)ppGpp is a nucleotide messenger universally produced in bacteria following nutrient starvation. In E. coli, ppGpp inhibits purine nucleotide synthesis by targeting several different enzymes, but the physiological significance of their inhibition is unknown. Here, we report the structural basis of inhibition for one target, Gsk, the inosine-guanosine kinase. Gsk creates an unprecedented, allosteric binding pocket for ppGpp by restructuring terminal sequences, which restrains conformational dynamics necessary for catalysis. Guided by this structure, we generated a chromosomal mutation that abolishes Gsk regulation by ppGpp. This mutant strain accumulates abnormally high levels of purine nucleotides following amino-acid starvation, compromising cellular fitness. We demonstrate that this unrestricted increase in purine nucleotides is detrimental because it severely depletes pRpp and essential, pRpp-derived metabolites, including UTP, histidine, and tryptophan. Thus, our results reveal the significance of ppGpp's regulation of purine nucleotide synthesis and a critical mechanism by which E. coli coordinates biosynthetic processes during starvation.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Howard Hughes Medical Institute
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.MOLCEL.2020.08.005
