Filamentation modulates allosteric regulation of PRPS.
Journal
eLife
Journal Volume
11
ISSN
2050-084X
Date Issued
2022-06-23
Author(s)
Hu, Huan-Huan
Lu, Guang-Ming
Li, Yilan
Zhong, Jiale
Guo, Chen-Jun
Zhou, Xian
Yin, Boqi
Zhang, Tianyi
Liu, Ji-Long
Abstract
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 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.
Subjects
Cryo-EM
E. coli
PRPS
allosteric regulation
cytoophidium
molecular biophysics
structural biology
Publisher
eLife Sciences
Description
Article number: e79552
Type
journal article