Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction
- University of Wisconsin-Madison, United States
Abstract
The alarmone (p)ppGpp regulates diverse targets, yet its target specificity and evolution remain poorly understood. Here we elucidate the mechanism by which basal (p)ppGpp inhibits the purine salvage enzyme HPRT by sharing a conserved motif with its substrate PRPP. Intriguingly, HPRT regulation by (p)ppGpp varies across organisms and correlates with HPRT oligomeric forms. (p)ppGpp-sensitive HPRT exists as a PRPP-bound dimer or an apo- and (p)ppGpp-bound tetramer, where a dimer-dimer interface triggers allosteric structural rearrangements to enhance (p)ppGpp inhibition. Loss of this oligomeric interface results in weakened (p)ppGpp regulation. Our results reveal an evolutionary principle whereby protein oligomerization allows evolutionary change to accumulate away from a conserved binding pocket to allosterically alter specificity of ligand interaction. This principle also explains how another (p)ppGpp target GMK is variably regulated across species. Since most ligands bind near protein interfaces, we propose that this principle extends to many other protein-ligand interactions.
Data availability
Diffraction data have been deposited in PDB under the accession codes 6D9Q (https://www.rcsb.org/structure/6d9q), 6D9R (https://www.rcsb.org/structure/6d9r), and 6D9S (https://www.rcsb.org/structure/6D9S). All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Table 2.
Article and author information
Author details
Kenneth A Satyshur
Funding
National Institute of General Medical Sciences (R35 GM127088)
- Jue D Wang
Howard Hughes Medical Institute (Faculty Scholar)
- Jue D Wang
National Science Foundation (GRFP DGE-1256259)
- Brent W Anderson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Anderson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction
eLife 8:e47534.
https://doi.org/10.7554/eLife.47534
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