Affinity-based capture and identification of protein effectors of the growth regulator ppGpp
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. Furthermore, the capture compounds developed should also enable the rapid identification of ppGpp targets in any species, including pathogens.
- Authors:
-
[1];
[4]
- Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
- Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Koch Inst. for Cancer Research
- Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Koch Inst. for Cancer Research; Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Center for Environmental Health Sciences; Broad Inst. of Harvard and MIT, Cambridge, MA (United States)
- Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Howard Hughes Medical Inst.
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE; National Science Foundation (NSF); National Institutes of Health (NIH)
- OSTI Identifier:
- 1569903
- Grant/Contract Number:
- AC02-06CH11357; NSF-0070319; R01GM082899
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Chemical Biology
- Additional Journal Information:
- Journal Volume: 15; Journal Issue: 2; Journal ID: ISSN 1552-4450
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Bacteria; Enzymes; Microbiology; Target identification; X-ray crystallography
Citation Formats
Wang, Boyuan, Dai, Peng, Ding, David, Del Rosario, Amanda, Grant, Robert A., Pentelute, Bradley L., and Laub, Michael T. Affinity-based capture and identification of protein effectors of the growth regulator ppGpp. United States: N. p., 2018.
Web. doi:10.1038/s41589-018-0183-4.
Wang, Boyuan, Dai, Peng, Ding, David, Del Rosario, Amanda, Grant, Robert A., Pentelute, Bradley L., & Laub, Michael T. Affinity-based capture and identification of protein effectors of the growth regulator ppGpp. United States. https://doi.org/10.1038/s41589-018-0183-4
Wang, Boyuan, Dai, Peng, Ding, David, Del Rosario, Amanda, Grant, Robert A., Pentelute, Bradley L., and Laub, Michael T. Mon .
"Affinity-based capture and identification of protein effectors of the growth regulator ppGpp". United States. https://doi.org/10.1038/s41589-018-0183-4. https://www.osti.gov/servlets/purl/1569903.
@article{osti_1569903,
title = {Affinity-based capture and identification of protein effectors of the growth regulator ppGpp},
author = {Wang, Boyuan and Dai, Peng and Ding, David and Del Rosario, Amanda and Grant, Robert A. and Pentelute, Bradley L. and Laub, Michael T.},
abstractNote = {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. Furthermore, the capture compounds developed should also enable the rapid identification of ppGpp targets in any species, including pathogens.},
doi = {10.1038/s41589-018-0183-4},
journal = {Nature Chemical Biology},
number = 2,
volume = 15,
place = {United States},
year = {Mon Dec 17 00:00:00 EST 2018},
month = {Mon Dec 17 00:00:00 EST 2018}
}
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