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Review
. 2020 Oct:66:28-33.
doi: 10.1016/j.ceb.2020.04.006. Epub 2020 May 14.

Filament formation by metabolic enzymes-A new twist on regulation

Eric M Lynch  1 , Justin M Kollman  2 , Bradley A Webb  3
Affiliations
Review

Filament formation by metabolic enzymes-A new twist on regulation

Eric M Lynch et al. Curr Opin Cell Biol. 2020 Oct.

Abstract

Compartmentalization of metabolic enzymes through protein-protein interactions is an emerging mechanism for localizing and regulating metabolic activity. Self-assembly into linear filaments is a common strategy for cellular compartmentalization of enzymes. Polymerization is often driven by changes in the metabolic state of the cell, suggesting that it is a strategy for shifting metabolic flux in response to cellular demand. Although polymerization of metabolic enzymes is widespread, observed from bacteria to humans, we are just beginning to appreciate their role in regulating cellular metabolism. In most cases, one functional role of metabolic enzyme filaments is allosteric control of enzyme activity. Here, we highlight recent findings, providing insight into the structural and functional significance of filamentation of metabolic enzymes in cells.

Keywords: Allostery; Cryogenic electron microscopy; Enzyme regulation; Filament formation; Metabolic enzyme; Self-assembly.

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Conflict of interest statement

Conflict of interest statement Nothing declared.

Figures

Figure 1.
Figure 1.. Filament formation has diverse effects on metabolic enzyme regulation.
(A) Yeast glucokinase 1 (Glk1) assembles into inactive filaments. Glk1 forms two-stranded filaments that selectively stabilize the closed conformation, inhibiting the enzyme by preventing conformational cycling. (B) Filament formation is essential to the activity of bacterial alcohol-aldehyde dehydrogenase (AdhE). The two AdhE active sites are in separate domains connected by a linker (pink). AdhE assembles into compressed filaments, which cooperatively extend into active filaments upon addition of cofactors. Two adjacent monomers are colored within each filament (monomer n; blue and monomer n+1; light blue), with the remainder of the filament in grey. In the active filament a tunnel connects sequential active sites, allowing efficient transfer of reaction intermediates. (C) Human CTP synthase 2 (CTPS2) filaments enable highly cooperative regulation. CTPS2 forms tetramers, which switch from an active to an inactive conformation upon binding their product, a feedback inhibitor. In the tetramer cooperative inhibition is limited to four protomers, while polymerization expands cooperativity by linking the conformational state of many tetramers, producing ultrasensitive regulation.
See this image and copyright information in PMC

References

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    1. Noree C et al. (2019) A quantitative screen for metabolic enzyme structures reveals patterns of assembly across the yeast metabolic network. - PMC - PubMed

    2. * In a large-scale screen of GFP-labeled proteins in yeast, the authors demonstrate that sixty metabolic enzymes form micrometer-sized assemblies, some of which dynamically assembled depending on the metabolic state of the cell. In certain pathways, multiple metabolic enzymes were observed to aggregate. Further, the ability to assemble was enriched in enzymes that catalyze branch point reactions in several metabolic pathways.

    1. Narayanaswamy R et al. (2009) Widespread reorganization of metabolic enzymes into reversible assemblies upon nutrient starvation. Proc. Natl. Acad. Sci. U.S.A 106, 10147–10152 - PMC - PubMed
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    2. ** Glucokinase catalyzes the ATP-dependent phosphorylation of glucose. The authors show that yeast glucokinase (Glk1) forms two-stranded filaments in which Glk1 is inactive. In cells, Glk1 forms filaments upon glucose addition, which disassemble upon glucose removal. The authors propose that filamentation of Glk1 is a mechanism regulating glucose phosphorylation by buffering the levels of active enzyme, thus setting the maximal rate of phosphorylation. This paper is an excellent example of structural biology informing cell biology.

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