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


ABSTRACT: 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 14-3-3?/? and ? 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.

SUBMITTER: Toleman CA 

PROVIDER: S-EPMC6003352 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Toleman Clifford A CA   Schumacher Maria A MA   Yu Seok-Ho SH   Zeng Wenjie W   Cox Nathan J NJ   Smith Timothy J TJ   Soderblom Erik J EJ   Wands Amberlyn M AM   Kohler Jennifer J JJ   Boyce Michael M  

Proceedings of the National Academy of Sciences of the United States of America 20180521 23


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  ...[more]

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