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Affinity-based capture and identification of protein effectors of the growth regulator ppGpp

Author(s)
Wang, Boyuan; Dai, Peng; Ding, David; Del Rosario, Amanda M; Grant, Robert A; Pentelute, Bradley L.; Laub, Michael T; ... Show more Show less
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Abstract
The nucleotide ppGpp is a highly conserved regulatory molecule in bacteria that helps tune growth rate to nutrient availability. Despite decades of study, how ppGpp regulates growth remains poorly understood. Here, we developed and validated a capture-compound mass spectrometry approach that identified >50 putative ppGpp targets in Escherichia coli. These targets control many key cellular processes and include 13 enzymes required for nucleotide synthesis. We demonstrated that ppGpp inhibits the de novo synthesis of all purine nucleotides by directly targeting the enzyme PurF. By solving a structure of PurF bound to ppGpp, we designed a mutation that ablates ppGpp-based regulation, leading to dysregulation of purine-nucleotide synthesis following ppGpp accumulation. Collectively, our results provide new insights into ppGpp-based growth control and a nearly comprehensive set of targets for future exploration. The capture compounds developed should also enable the rapid identification of ppGpp targets in any species, including pathogens. Keywords: bacteria; enzymes; microbiology; target identification; x-ray crystallography
Date issued
2018-12
URI
https://hdl.handle.net/1721.1/123670
Department
Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Chemistry; Massachusetts Institute of Technology. Center for Environmental Health Sciences; Koch Institute for Integrative Cancer Research at MIT
Journal
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Citation
Wang, Boyuan et al. "Affinity-based capture and identification of protein effectors of the growth regulator ppGpp." Nature Chemical Biology 15, 2 (December 2018): 141–150 © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
Version: Author's final manuscript
ISSN
1552-4450
1552-4469

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