Filamentation modulates allosteric regulation of PRPS
- ShanghaiTech University, China
Abstract
Phosphoribosyl pyrophosphate (PRPP) is a key intermediate in the biosynthesis of purine and pyrimidine nucleotides, histidine, tryptophan, and cofactors NAD and NADP. Abnormal regulation of PRPP synthase (PRPS) is associated with human disorders, including Arts syndrome, retinal dystrophy and gouty arthritis. Recent studies have demonstrated that PRPS can form filamentous cytoophidia in eukaryotes. Here we show that PRPS forms cytoophidia in prokaryotes both in vitro and in vivo. Moreover, we solve two distinct filament structures of E. coli PRPS at near-atomic resolution under Cryo-EM. The formation of the two types of filaments is controlled by the binding of different ligands. One filament type is resistant to allosteric inhibition. The structural comparison reveals conformational changes of a regulatory flexible loop, which may regulate the binding of the allosteric inhibitor and the substrate ATP. A noncanonical allosteric AMP/ADP binding site is identified to stabilize the conformation of the regulatory flexible loop. Our findings not only explore a new mechanism of PRPS regulation with structural basis, but also propose an additional layer of cell metabolism through PRPS filamentation.
Data availability
Atomic models generated in this study have been deposited at thePDB under the accession codes 7XMU, 7XMV, 7XN3. Cryo-EMmaps deposited to EMDB as: EMD-33305, EMD-33306, EMD-33309.
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E.coli phosphoribosylpyrophosphate (PRPP) synthetase type B filament bound with Pi.RCSB Protein Data Bank, 7XN3.
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E.coli phosphoribosylpyrophosphate (PRPP) synthetase type A filament bound with ADP, Pi and R5P.Electron Microscopy Data Bank, EMD-33305.
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E.coli phosphoribosylpyrophosphate (PRPP) synthetase type A (AMP/ADP) filament bound with ADP, AMP and R5P.Electron Microscopy Data Bank, EMD-33306.
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E.coli phosphoribosylpyrophosphate (PRPP) synthetase type B filament bound with Pi.Electron Microscopy Data Bank, EMD-33309.
Article and author information
Author details
Funding
Ministry of Science and Technology of the People's Republic of China (2021YFA0804701-4)
- Ji-Long Liu
National Natural Science Foundation of China (31771490)
- Ji-Long Liu
Shanghai Science and Technology Commission (20JC1410500)
- Ji-Long Liu
Medical Research Council (MC_UU_12021/3; MC_U137788471)
- Ji-Long Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Hu 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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Filamentation modulates allosteric regulation of PRPS
eLife 11:e79552.
https://doi.org/10.7554/eLife.79552
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