Structural basis of human PRPS2 filaments

作者：Guangming Lu, Huan-Huan Hu, Chia‐Chun Chang, Jiale Zhong, Xian Zhou, Chen-Jun Guo, Tianyi Zhang, Yi‐Lan Li, Boqi Yin, Ji‐Long Liu · 发表于：Cell & Bioscience · 年份：2023 · DOI：10.1186/s13578-023-01037-z · 被引用次数：22 · 研究领域：Protein Kinase Regulation and GTPase Signaling、Protein Tyrosine Phosphatases、Protease and Inhibitor Mechanisms

Abstract 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 inte...