Dynamic Reorganization of Metabolic Enzymes into Intracellular Bodies

Abstract

Both focused and large-scale cell biological and biochemical studies have revealed that hundreds of metabolic enzymes across diverse organisms form large intracellular bodies. These proteinaceous bodies range in form from fibers and intracellular foci—such as those formed by enzymes of nitrogen and carbon utilization and of nucleotide biosynthesis—to high-density packings inside bacterial microcompartments and eukaryotic microbodies. Although many enzymes clearly form functional mega-assemblies, it is not yet clear for many recently discovered cases whether they represent functional entities, storage bodies, or aggregates. In this article, we survey intracellular protein bodies formed by metabolic enzymes, asking when and why such bodies form and what their formation implies for the functionality—and dysfunctionality—of the enzymes that comprise them. The panoply of intracellular protein bodies also raises interesting questions regarding their evolution and maintenance within cells. We speculate on models for how such structures form in the first place and why they may be inevitable.

Ultrastructure of Cytoplasmic and Nuclear Inosine-5’-Monophosphate Dehydrogenase 2 “Rods and Rings” Inclusions

“…The ability of some other metabolic enzymes to form cellular inclusions has been reported by many groups (reviewed in O'Connell et al 2012). The formation of enzyme inclusions seems to be phylogenetically conserved, as these structures have been noted in many organisms, from bacteria to mammals (Ingerson-Mahar et al 2010;Liu 2010;Noree et al 2010;Carcamo et al 2011;Chen et al 2011;Liu 2011).…”

“…However, the reason for the formation of these filamentous structures remains unknown. O'Connell et al (2012) speculated that some of these inclusions could be the result of the self-assembly of enzymes, as they frequently exhibit a high level of protein self-organization. This is in agreement with our results (Supplemental Fig.…”

The Glycolytic Enzyme Phosphofructokinase-1 Assembles into Filaments

“…Filament assembly has been reported for several mammalian cytosolic metabolic enzymes, including acetyl-coA carboxylase (Meredith and Lane, 1978;Beaty and Lane, 1983), glutamine synthase (Frey et al, 1975), glutamate dehydrogenase (Eisenberg and Tomkins, 1968;Cohen et al, 1976), glutaminase (Olsen et al, 1970), β-glucosidase (Gunning, 1965;Kim et al, 2005), and cytidine triphosphate (CTP) synthase (Ingerson-Mahar et al, 2010;Liu, 2010;Noree et al, 2010;Habrian et al, 2016). Filament assembly by metabolic enzymes is not restricted to mammalian cells but is also seen in yeasts and bacteria (O'Connell et al, 2012;Shen et al, 2016), suggesting conserved biological processes. Several not necessarily exclusive functions for the evolution of metabolic enzyme filaments from bacteria to mammalian cells have been proposed (O'Connell et al, 2012).…”

“…Filament assembly by metabolic enzymes is not restricted to mammalian cells but is also seen in yeasts and bacteria (O'Connell et al, 2012;Shen et al, 2016), suggesting conserved biological processes. Several not necessarily exclusive functions for the evolution of metabolic enzyme filaments from bacteria to mammalian cells have been proposed (O'Connell et al, 2012). In some cases, assembly has a direct effect on enzyme activity and is believed to provide an additional layer of regulation in response to changing metabolic conditions; for example, bacterial CTP synthase is inactivated in the filament form (Barry et al, 2014).…”

Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

“…In fact, protein phase separation has been invoked as mechanism underlying the formation of various subcellular foci and puncta. 3 The emphasis of this paper is on protein self-assembly during amyloid fibril formation. Amyloid fibril deposits have been linked to an ever-increasing variety of human pathologies ranging from Alzheimer's disease over type II diabetes to rheumatoid arthritis.…”