Structural basis of human PRPS2 filaments

Cell & Bioscience

Research

Chia-Chun Chang¹  Xian Zhou¹  Yi-Lan Li¹  Boqi Yin¹  Chen-Jun Guo¹  Tianyi Zhang¹  Guang-Ming Lu¹  Jiale Zhong¹  Huan-Huan Hu¹  Ji-Long Liu² 

[1]School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China

[2]School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China

[3]Department of Physiology, Anatomy and Genetics, University of Oxford, OX1 3PT, Oxford, UK

关键词: PRPS;    PRPP;    Cytoophidium;    hPRPS2;    Cryo-EM;    Allosteric regulation;   

DOI  :  10.1186/s13578-023-01037-z

 received in 2023-01-04, accepted in 2023-04-19,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPRPP 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.ResultsOrder 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.ConclusionFindings suggest that the regulation of hPRPS2 polymer is distinct from ecPRPS polymer and provide new insights to the regulation of hPRPS2 with structural basis.

【 授权许可】

CC BY   
© The Author(s) 2023

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