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Filamentation modulates allosteric regulation of PRPS.

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 E. coli 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.

SUBMITTER: Hu HH

PROVIDER: S-EPMC9232217 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Filamentation modulates allosteric regulation of PRPS.

Hu Huan-Huan HH Lu Guang-Ming GM Chang Chia-Chun CC Li Yilan Y Zhong Jiale J Guo Chen-Jun CJ Zhou Xian X Yin Boqi B Zhang Tianyi T Liu Ji-Long JL

eLife 20220623

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 ...[more]

PMID: 35736577

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Project description:Candida albicans filamentation, the ability to convert from oval yeast cells to elongated hyphal cells, is a key factor in its pathogenesis. Previous work has shown that the integral membrane protein Dfi1 is required for filamentation in cells grown in contact with a semisolid surface. Investigations into the downstream targets of the Dfi1 pathway revealed potential links to two transcription factors, Sef1 and Czf1. Sef1 regulates iron uptake and iron utilization genes under low-iron conditions, leading us to hypothesize that there exists a link between iron availability and contact-dependent invasive filamentation. In this study, we showed that Sef1 was not required for contact-dependent filamentation, but it was required for wild-type (WT) expression levels of a number of genes during growth under contact conditions. Czf1 is required for contact-dependent filamentation and for WT levels of expression of several genes. Constitutive expression and activation of either Sef1 or Czf1 individually in a dfi1 null strain resulted in a complete rescue of the dfi1 null filamentation defect. Because Sef1 is normally activated in low-iron environments, we embedded WT and dfi1 null cells in iron-free agar medium supplemented with various concentrations of ferrous ammonium sulfate (FAS). dfi1 null cells embedded in media with a low concentration of iron (20 μM FAS) showed increased filamentation in comparison to mutant cells embedded in higher concentrations of iron (50 to 500 μM). WT cells produced filamentous colonies in all concentrations. Together, the data indicate that Dfi1, Czf1, Sef1, and environmental iron regulate C. albicans contact-dependent filamentation. IMPORTANCE Candida albicans is an opportunistic pathogen responsible for a larger proportion of candidiasis and candidemia cases than any other Candida species. The ability of C. albicans cells to invade and cause disease is linked to their ability to filament. Despite this, there are gaps in our knowledge of the environmental cues and intracellular signaling that triggers the switch from commensal organism to filamentous pathogen. In this study, we identified a link between contact-dependent filamentation and iron availability. Over the course of tissue invasion, C. albicans cells encounter a number of different iron microenvironments, from the iron-rich gut to iron-poor tissues. Increased expression of Sef1-dependent iron uptake genes as a result of contact-dependent signaling will promote the adaptation of C. albicans cells to a low-iron-availability environment.

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Filamentation modulates allosteric regulation of PRPS.

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Filamentation modulates allosteric regulation of PRPS.

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