RT Journal Article
SR Electronic
T1 Allosteric inhibition of PRPS is moderated by filamentous polymerization
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.28.489849
DO 10.1101/2022.04.28.489849
A1 Huan-Huan Hu
A1 Guangming Lu
A1 Chia-Chun Chang
A1 Yilan Li
A1 Jiale Zhong
A1 Chen-Jun Guo
A1 Xian Zhou
A1 Boqi Yin
A1 Tianyi Zhang
A1 Ji-Long Liu
YR 2022
UL http://biorxiv.org/content/early/2022/04/28/2022.04.28.489849.abstract
AB Phosphoribosyl pyrophosphate (PRPP) is an important intermediate for the biosynthesis of purine and pyrimidine nucleotides, histidine, tryptophan, and cofactors NAD and NADP. Abnormal regulation of PRPP synthase (PRPS) has been associated with human disorders including Arts syndrome, retinal dystrophy and gouty arthritis. Recent studies have revealed that PRPS can form filamentous cytoophidia in prokaryotes and eukaryotes. Here we resolve two distinct filament structures of E. coli PRPS at near-atomic resolution under Cryo-EM. Formation of two types of filaments is controlled by the binding of different ligands. While the type A filament attenuates the allosteric inhibition of PRPS by ADP, the type B filament enhances the inhibition. In addition, a novel conformation of the regulatory flexible loop of PRPS was found occupying the ATP binding site. AMP/ADP bound at a noncanonical allosteric site interacts with the regulatory flexible loop and facilitates the binding of ATP. Our findings not only reveal molecular mechanisms of the regulation of PRPS with structural basis, but also suggest a distinctive bidirectional regulatory system for PRPP production via PRPS polymerization.Competing Interest StatementThe authors have declared no competing interest.