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A little sugar goes a long way: the cell biology of O-GlcNAc.

Bond MR, Hanover JA - J. Cell Biol. (2015)

Bottom Line: Alternative splicing of the genes encoding the O-GlcNAc cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) yields isoforms targeted to discrete sites in the nucleus, cytoplasm, and mitochondria.OGT and OGA also partner with cellular effectors and act in tandem with other posttranslational modifications.The enzymes of O-GlcNAc cycling act preferentially on intrinsically disordered domains of target proteins impacting transcription, metabolism, apoptosis, organelle biogenesis, and transport.

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ABSTRACT
Unlike the complex glycans decorating the cell surface, the O-linked β-N-acetyl glucosamine (O-GlcNAc) modification is a simple intracellular Ser/Thr-linked monosaccharide that is important for disease-relevant signaling and enzyme regulation. O-GlcNAcylation requires uridine diphosphate-GlcNAc, a precursor responsive to nutrient status and other environmental cues. Alternative splicing of the genes encoding the O-GlcNAc cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) yields isoforms targeted to discrete sites in the nucleus, cytoplasm, and mitochondria. OGT and OGA also partner with cellular effectors and act in tandem with other posttranslational modifications. The enzymes of O-GlcNAc cycling act preferentially on intrinsically disordered domains of target proteins impacting transcription, metabolism, apoptosis, organelle biogenesis, and transport.

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O-GlcNAc dynamically impacts biological homeostasis and disease pathologies by integrating environmental and genetic information. (A) The ubiquitous and essential modification of protein serine and threonine residues with O-GlcNAc modulates cellular biology by responding to variable nutrient conditions and integrating cellular programs to respond through nutrient-sensing and -managing networks. By targeting OGT and OGA to discrete intracellular sites, O-GlcNAcylation of diverse proteins (pink hexagon) influences the physiology of processes including memory, metabolism, and immunity. Aberrant O-GlcNAc modification is implicated in pathologies of metabolic and neurodegenertive diseases as well as cancers and autoimmunity. OIP, OGT interacting protein. (B) The O-GlcNAc and O-phosphate modifications share some characteristics but differ in others.
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fig1: O-GlcNAc dynamically impacts biological homeostasis and disease pathologies by integrating environmental and genetic information. (A) The ubiquitous and essential modification of protein serine and threonine residues with O-GlcNAc modulates cellular biology by responding to variable nutrient conditions and integrating cellular programs to respond through nutrient-sensing and -managing networks. By targeting OGT and OGA to discrete intracellular sites, O-GlcNAcylation of diverse proteins (pink hexagon) influences the physiology of processes including memory, metabolism, and immunity. Aberrant O-GlcNAc modification is implicated in pathologies of metabolic and neurodegenertive diseases as well as cancers and autoimmunity. OIP, OGT interacting protein. (B) The O-GlcNAc and O-phosphate modifications share some characteristics but differ in others.

Mentions: Protein modification by O-linked β-N-acetyl glucosamine (O-GlcNAc) has rapidly emerged as a major cellular signaling mechanism rivaling protein phosphorylation in terms of the number of modified targets (Fig. 1 A). O-GlcNAc is an uncharged acetylated hexosamine sugar attached through a glycosyl linkage to hydroxyl-containing amino acids that adds bulk to modified amino acid side chains. O-GlcNAc is added to and removed from nucleocytoplasmic and mitochondrial target proteins by the intracellular enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). These O-GlcNAc cycling enzymes are distinct from the glycosyltransferases and glycosidases sequestered within the lumen of endomembrane organelles or routed to the cell surface. The enzymatic machinery catalyzing O-GlcNAc addition and removal bear some structural resemblance to nucleocytoplasmic kinases and phosphatases. In fact, there are many parallels between phosphorylation and O-GlcNAcylation: O-GlcNAc is added to Ser and Thr residues; the modification rapidly cycles on and off modified proteins at a rate faster than protein turnover; and like kinases and phosphatases, OGT and OGA are phosphorylated (Fig. 1 B; Butkinaree et al., 2010; Hanover et al., 2010). Many target proteins are modified by both O-GlcNAc and phosphate at exposed regions, suggesting the presence of shared or coexisting recognition motifs. However, although the sites of protein phosphorylation can often be identified by primary sequence alone, O-GlcNAcylation is not associated with a clear consensus motif.


A little sugar goes a long way: the cell biology of O-GlcNAc.

Bond MR, Hanover JA - J. Cell Biol. (2015)

O-GlcNAc dynamically impacts biological homeostasis and disease pathologies by integrating environmental and genetic information. (A) The ubiquitous and essential modification of protein serine and threonine residues with O-GlcNAc modulates cellular biology by responding to variable nutrient conditions and integrating cellular programs to respond through nutrient-sensing and -managing networks. By targeting OGT and OGA to discrete intracellular sites, O-GlcNAcylation of diverse proteins (pink hexagon) influences the physiology of processes including memory, metabolism, and immunity. Aberrant O-GlcNAc modification is implicated in pathologies of metabolic and neurodegenertive diseases as well as cancers and autoimmunity. OIP, OGT interacting protein. (B) The O-GlcNAc and O-phosphate modifications share some characteristics but differ in others.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384737&req=5

fig1: O-GlcNAc dynamically impacts biological homeostasis and disease pathologies by integrating environmental and genetic information. (A) The ubiquitous and essential modification of protein serine and threonine residues with O-GlcNAc modulates cellular biology by responding to variable nutrient conditions and integrating cellular programs to respond through nutrient-sensing and -managing networks. By targeting OGT and OGA to discrete intracellular sites, O-GlcNAcylation of diverse proteins (pink hexagon) influences the physiology of processes including memory, metabolism, and immunity. Aberrant O-GlcNAc modification is implicated in pathologies of metabolic and neurodegenertive diseases as well as cancers and autoimmunity. OIP, OGT interacting protein. (B) The O-GlcNAc and O-phosphate modifications share some characteristics but differ in others.
Mentions: Protein modification by O-linked β-N-acetyl glucosamine (O-GlcNAc) has rapidly emerged as a major cellular signaling mechanism rivaling protein phosphorylation in terms of the number of modified targets (Fig. 1 A). O-GlcNAc is an uncharged acetylated hexosamine sugar attached through a glycosyl linkage to hydroxyl-containing amino acids that adds bulk to modified amino acid side chains. O-GlcNAc is added to and removed from nucleocytoplasmic and mitochondrial target proteins by the intracellular enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). These O-GlcNAc cycling enzymes are distinct from the glycosyltransferases and glycosidases sequestered within the lumen of endomembrane organelles or routed to the cell surface. The enzymatic machinery catalyzing O-GlcNAc addition and removal bear some structural resemblance to nucleocytoplasmic kinases and phosphatases. In fact, there are many parallels between phosphorylation and O-GlcNAcylation: O-GlcNAc is added to Ser and Thr residues; the modification rapidly cycles on and off modified proteins at a rate faster than protein turnover; and like kinases and phosphatases, OGT and OGA are phosphorylated (Fig. 1 B; Butkinaree et al., 2010; Hanover et al., 2010). Many target proteins are modified by both O-GlcNAc and phosphate at exposed regions, suggesting the presence of shared or coexisting recognition motifs. However, although the sites of protein phosphorylation can often be identified by primary sequence alone, O-GlcNAcylation is not associated with a clear consensus motif.

Bottom Line: Alternative splicing of the genes encoding the O-GlcNAc cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) yields isoforms targeted to discrete sites in the nucleus, cytoplasm, and mitochondria.OGT and OGA also partner with cellular effectors and act in tandem with other posttranslational modifications.The enzymes of O-GlcNAc cycling act preferentially on intrinsically disordered domains of target proteins impacting transcription, metabolism, apoptosis, organelle biogenesis, and transport.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
Unlike the complex glycans decorating the cell surface, the O-linked β-N-acetyl glucosamine (O-GlcNAc) modification is a simple intracellular Ser/Thr-linked monosaccharide that is important for disease-relevant signaling and enzyme regulation. O-GlcNAcylation requires uridine diphosphate-GlcNAc, a precursor responsive to nutrient status and other environmental cues. Alternative splicing of the genes encoding the O-GlcNAc cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) yields isoforms targeted to discrete sites in the nucleus, cytoplasm, and mitochondria. OGT and OGA also partner with cellular effectors and act in tandem with other posttranslational modifications. The enzymes of O-GlcNAc cycling act preferentially on intrinsically disordered domains of target proteins impacting transcription, metabolism, apoptosis, organelle biogenesis, and transport.

Show MeSH
Related in: MedlinePlus