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Structural basis of human PRPS2 filaments
BACKGROUND: PRPP synthase (PRPS) transfers the pyrophosphate groups from ATP to ribose-5-phosphate to produce 5-phosphate ribose-1-pyrophosphate (PRPP), a key intermediate in the biosynthesis of several metabolites including nucleotides, dinucleotides and some amino acids. There are three PRPS isofo...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10227994/ https://www.ncbi.nlm.nih.gov/pubmed/37248548 http://dx.doi.org/10.1186/s13578-023-01037-z |
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author | Lu, Guang-Ming Hu, Huan-Huan Chang, Chia-Chun Zhong, Jiale Zhou, Xian Guo, Chen-Jun Zhang, Tianyi Li, Yi-Lan Yin, Boqi Liu, Ji-Long |
author_facet | Lu, Guang-Ming Hu, Huan-Huan Chang, Chia-Chun Zhong, Jiale Zhou, Xian Guo, Chen-Jun Zhang, Tianyi Li, Yi-Lan Yin, Boqi Liu, Ji-Long |
author_sort | Lu, Guang-Ming |
collection | PubMed |
description | BACKGROUND: PRPP synthase (PRPS) transfers the pyrophosphate groups from ATP to ribose-5-phosphate to produce 5-phosphate ribose-1-pyrophosphate (PRPP), a key intermediate in the biosynthesis of several metabolites including nucleotides, dinucleotides and some amino acids. There are three PRPS isoforms encoded in human genome. While human PRPS1 (hPRPS1) and human PRPS2 (hPRPS2) are expressed in most tissues, human PRPS3 (hPRPS3) is exclusively expressed in testis. Although hPRPS1 and hPRPS2 share 95% sequence identity, hPRPS2 has been shown to be less sensitive to allosteric inhibition and specifically upregulated in certain cancers in the translational level. Recent studies demonstrate that PRPS can form a subcellular compartment termed the cytoophidium in multiple organisms across prokaryotes and eukaryotes. Forming filaments and cytoophidia is considered as a distinctive mechanism involving the polymerization of the protein. Previously we solved the filament structures of Escherichia coli PRPS (ecPRPS) using cryo-electron microscopy (cryo-EM) (1). RESULTS: Order to investigate the function and molecular mechanism of hPRPS2 polymerization, here we solve the polymer structure of hPRPS2 at 3.08 Å resolution. hPRPS2 hexamers stack into polymers in the conditions with the allosteric/competitive inhibitor ADP. The binding modes of ADP at the canonical allosteric site and at the catalytic active site are clearly determined. A point mutation disrupting the inter-hexamer interaction prevents hPRPS2 polymerization and results in significantly reduced catalytic activity. CONCLUSION: Findings suggest that the regulation of hPRPS2 polymer is distinct from ecPRPS polymer and provide new insights to the regulation of hPRPS2 with structural basis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01037-z. |
format | Online Article Text |
id | pubmed-10227994 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-102279942023-05-31 Structural basis of human PRPS2 filaments Lu, Guang-Ming Hu, Huan-Huan Chang, Chia-Chun Zhong, Jiale Zhou, Xian Guo, Chen-Jun Zhang, Tianyi Li, Yi-Lan Yin, Boqi Liu, Ji-Long Cell Biosci Research BACKGROUND: PRPP synthase (PRPS) transfers the pyrophosphate groups from ATP to ribose-5-phosphate to produce 5-phosphate ribose-1-pyrophosphate (PRPP), a key intermediate in the biosynthesis of several metabolites including nucleotides, dinucleotides and some amino acids. There are three PRPS isoforms encoded in human genome. While human PRPS1 (hPRPS1) and human PRPS2 (hPRPS2) are expressed in most tissues, human PRPS3 (hPRPS3) is exclusively expressed in testis. Although hPRPS1 and hPRPS2 share 95% sequence identity, hPRPS2 has been shown to be less sensitive to allosteric inhibition and specifically upregulated in certain cancers in the translational level. Recent studies demonstrate that PRPS can form a subcellular compartment termed the cytoophidium in multiple organisms across prokaryotes and eukaryotes. Forming filaments and cytoophidia is considered as a distinctive mechanism involving the polymerization of the protein. Previously we solved the filament structures of Escherichia coli PRPS (ecPRPS) using cryo-electron microscopy (cryo-EM) (1). RESULTS: Order to investigate the function and molecular mechanism of hPRPS2 polymerization, here we solve the polymer structure of hPRPS2 at 3.08 Å resolution. hPRPS2 hexamers stack into polymers in the conditions with the allosteric/competitive inhibitor ADP. The binding modes of ADP at the canonical allosteric site and at the catalytic active site are clearly determined. A point mutation disrupting the inter-hexamer interaction prevents hPRPS2 polymerization and results in significantly reduced catalytic activity. CONCLUSION: Findings suggest that the regulation of hPRPS2 polymer is distinct from ecPRPS polymer and provide new insights to the regulation of hPRPS2 with structural basis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01037-z. BioMed Central 2023-05-30 /pmc/articles/PMC10227994/ /pubmed/37248548 http://dx.doi.org/10.1186/s13578-023-01037-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Lu, Guang-Ming Hu, Huan-Huan Chang, Chia-Chun Zhong, Jiale Zhou, Xian Guo, Chen-Jun Zhang, Tianyi Li, Yi-Lan Yin, Boqi Liu, Ji-Long Structural basis of human PRPS2 filaments |
title | Structural basis of human PRPS2 filaments |
title_full | Structural basis of human PRPS2 filaments |
title_fullStr | Structural basis of human PRPS2 filaments |
title_full_unstemmed | Structural basis of human PRPS2 filaments |
title_short | Structural basis of human PRPS2 filaments |
title_sort | structural basis of human prps2 filaments |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10227994/ https://www.ncbi.nlm.nih.gov/pubmed/37248548 http://dx.doi.org/10.1186/s13578-023-01037-z |
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