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EMBO J. 2008 Oct 22;27(20):2780-8. doi: 10.1038/emboj.2008.186. Epub 2008 Sep 25.

Structural insights into mechanism and specificity of O-GlcNAc transferase.

Author information

1
Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.

Abstract

Post-translational modification of protein serines/threonines with N-acetylglucosamine (O-GlcNAc) is dynamic, inducible and abundant, regulating many cellular processes by interfering with protein phosphorylation. O-GlcNAcylation is regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase, both encoded by single, essential, genes in metazoan genomes. It is not understood how OGT recognises its sugar nucleotide donor and performs O-GlcNAc transfer onto proteins/peptides, and how the enzyme recognises specific cellular protein substrates. Here, we show, by X-ray crystallography and mutagenesis, that OGT adopts the (metal-independent) GT-B fold and binds a UDP-GlcNAc analogue at the bottom of a highly conserved putative peptide-binding groove, covered by a mobile loop. Strikingly, the tetratricopeptide repeats (TPRs) tightly interact with the active site to form a continuous 120 A putative interaction surface, whereas the previously predicted phosphatidylinositide-binding site locates to the opposite end of the catalytic domain. On the basis of the structure, we identify truncation/point mutants of the TPRs that have differential effects on activity towards proteins/peptides, giving first insights into how OGT may recognise its substrates.

PMID:
18818698
PMCID:
PMC2556091
DOI:
10.1038/emboj.2008.186
[Indexed for MEDLINE]
Free PMC Article

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