6IBO

Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability

6IBO の概要

• エントリーDOI: 10.2210/pdb6ibo/pdb
• 分子名称: UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit, ALA-VAL-SER-ARG-ALA, (2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-thiopyran-2-yl [(2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl dihydrogen diphosphate, ... (5 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82735.09

構造登録者

Gundogdu, M.,van Aalten, D.M.F. (登録日: 2018-11-30, 公開日: 2019-07-24, 最終更新日: 2024-01-24)

主引用文献

Pravata, V.M.,Muha, V.,Gundogdu, M.,Ferenbach, A.T.,Kakade, P.S.,Vandadi, V.,Wilmes, A.C.,Borodkin, V.S.,Joss, S.,Stavridis, M.P.,van Aalten, D.M.F.
Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability.
Proc.Natl.Acad.Sci.USA, 116:14961-14970, 2019

PubMed Abstract: O-GlcNAc transferase (OGT) is an X-linked gene product that is essential for normal development of the vertebrate embryo. It catalyses the O-GlcNAc posttranslational modification of nucleocytoplasmic proteins and proteolytic maturation of the transcriptional coregulator Host cell factor 1 (HCF1). Recent studies have suggested that conservative missense mutations distal to the OGT catalytic domain lead to X-linked intellectual disability in boys, but it is not clear if this is through changes in the O-GlcNAc proteome, loss of protein-protein interactions, or misprocessing of HCF1. Here, we report an OGT catalytic domain missense mutation in monozygotic female twins (c. X:70779215 T > A, p. N567K) with intellectual disability that allows dissection of these effects. The patients show limited IQ with developmental delay and skewed X-inactivation. Molecular analyses revealed decreased OGT stability and disruption of the substrate binding site, resulting in loss of catalytic activity. Editing this mutation into the genome results in global changes in the O-GlcNAc proteome, while in mouse embryonic stem cells it leads to loss of O-GlcNAcase and delayed differentiation down the neuronal lineage. These data imply that catalytic deficiency of OGT could contribute to X-linked intellectual disability.

PubMed: 31296563
DOI: 10.1073/pnas.1900065116

実験手法

X-RAY DIFFRACTION (2.17 Å)