Structural basis of O-GlcNAc recognition by mammalian 14-3-3 proteins

O-GlcNAc is an intracellular posttranslational modification that governs myriad cell biological processes and is dysregulated in human diseases. Despite this broad pathophysiological significance, the biochemical effects of most O-GlcNAcylation events remain uncharacterized. One prevalent hypothesis...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2018-06, Vol.115 (23), p.5956-5961
Main Authors: Toleman, Clifford A., Schumacher, Maria A., Yu, Seok-Ho, Zeng, Wenjie, Cox, Nathan J., Smith, Timothy J., Soderblom, Erik J., Wands, Amberlyn M., Kohler, Jennifer J., Boyce, Michael
Format: Article
Language:English
Subjects:
14-3-3 protein
14-3-3 Proteins - chemistry
14-3-3 Proteins - metabolism
Acetylglucosamine - chemistry
Acetylglucosamine - metabolism
Biological activity
Biological Sciences
Downstream effects
Glycopeptides
HEK293 Cells
Homocysteine
Humans
Information processing
Isoforms
Mass Spectrometry
Membranes
Models, Molecular
O-GlcNAcylation
Phosphopyruvate Hydratase - chemistry
Phosphopyruvate Hydratase - metabolism
Phosphorylation
Protein interaction
Proteins
Proteomics
Serine
Signaling
Sugar
Threonine
Transportation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:O-GlcNAc is an intracellular posttranslational modification that governs myriad cell biological processes and is dysregulated in human diseases. Despite this broad pathophysiological significance, the biochemical effects of most O-GlcNAcylation events remain uncharacterized. One prevalent hypothesis is that O-GlcNAc moieties may be recognized by “reader” proteins to effect downstream signaling. However, no general O-GlcNAc readers have been identified, leaving a considerable gap in the field. To elucidate O-GlcNAc signaling mechanisms, we devised a biochemical screen for candidate O-GlcNAc reader proteins. We identified several human proteins, including 14-3-3 isoforms, that bind O-GlcNAc directly and selectively. We demonstrate that 14-3-3 proteins bind O-GlcNAc moieties in human cells, and we present the structures of 14-3-3β/α and γ bound to glycopeptides, providing biophysical insights into O-GlcNAc-mediated protein–protein interactions. Because 14-3-3 proteins also bind to phospho-serine and phospho-threonine, they may integrate information from O-GlcNAc and O-phosphate signaling pathways to regulate numerous physiological functions.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1722437115