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Filamentation modulates allosteric regulation of PRPS

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...

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Autores principales: Hu, Huan-Huan, Lu, Guang-Ming, Chang, Chia-Chun, Li, Yilan, Zhong, Jiale, Guo, Chen-Jun, Zhou, Xian, Yin, Boqi, Zhang, Tianyi, Liu, Ji-Long
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9232217/
https://www.ncbi.nlm.nih.gov/pubmed/35736577
http://dx.doi.org/10.7554/eLife.79552
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author Hu, Huan-Huan
Lu, Guang-Ming
Chang, Chia-Chun
Li, Yilan
Zhong, Jiale
Guo, Chen-Jun
Zhou, Xian
Yin, Boqi
Zhang, Tianyi
Liu, Ji-Long
author_facet Hu, Huan-Huan
Lu, Guang-Ming
Chang, Chia-Chun
Li, Yilan
Zhong, Jiale
Guo, Chen-Jun
Zhou, Xian
Yin, Boqi
Zhang, Tianyi
Liu, Ji-Long
author_sort Hu, Huan-Huan
collection PubMed
description 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 using 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.
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spelling pubmed-92322172022-06-25 Filamentation modulates allosteric regulation of PRPS Hu, Huan-Huan Lu, Guang-Ming Chang, Chia-Chun Li, Yilan Zhong, Jiale Guo, Chen-Jun Zhou, Xian Yin, Boqi Zhang, Tianyi Liu, Ji-Long eLife Structural Biology and Molecular Biophysics 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 using 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. eLife Sciences Publications, Ltd 2022-06-23 /pmc/articles/PMC9232217/ /pubmed/35736577 http://dx.doi.org/10.7554/eLife.79552 Text en © 2022, Hu, Lu, Chang et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Hu, Huan-Huan
Lu, Guang-Ming
Chang, Chia-Chun
Li, Yilan
Zhong, Jiale
Guo, Chen-Jun
Zhou, Xian
Yin, Boqi
Zhang, Tianyi
Liu, Ji-Long
Filamentation modulates allosteric regulation of PRPS
title Filamentation modulates allosteric regulation of PRPS
title_full Filamentation modulates allosteric regulation of PRPS
title_fullStr Filamentation modulates allosteric regulation of PRPS
title_full_unstemmed Filamentation modulates allosteric regulation of PRPS
title_short Filamentation modulates allosteric regulation of PRPS
title_sort filamentation modulates allosteric regulation of prps
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9232217/
https://www.ncbi.nlm.nih.gov/pubmed/35736577
http://dx.doi.org/10.7554/eLife.79552
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