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

Clifford A. Toleman, Maria A. Schumacher, Seok Ho Yu, Wenjie Zeng, Nathan J. Cox, Timothy J. Smith, Erik J. Soderblom, Amberlyn M. Wands, Jennifer J. Kohler, Michael Boyce

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 unchar-acterized. 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.

Original languageEnglish (US)
Pages (from-to)5956-5961
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number23
DOIs
StatePublished - Jun 5 2018

Keywords

  • 14-3-3
  • EBP1
  • Enolase
  • O-GlcNAc
  • Reader proteins

ASJC Scopus subject areas

  • General

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