4CUF

Human Notch1 EGF domains 11-13 mutant T466S

4CUF の概要

• エントリーDOI: 10.2210/pdb4cuf/pdb
• 関連するPDBエントリー: 4CUD 4CUE
• 分子名称: NEUROGENIC LOCUS NOTCH HOMOLOG PROTEIN 1, CALCIUM ION, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: transcription, metal-binding, transmembrane, developmental, protein, notch signaling pathway, differentiation, phosphorylation, egf-like domain, regulation, receptor, activator, ank repeat, signalling, glycoprotein, extracellular, egf, jagged, nucleus, membrane
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cell membrane ; Single-pass type I membrane protein . Notch 1 intracellular domain: Nucleus : P46531
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15025.88

構造登録者

Taylor, P.,Takeuchi, H.,Sheppard, D.,Chillakuri, C.,Lea, S.M.,Haltiwanger, R.S.,Handford, P.A. (登録日: 2014-03-18, 公開日: 2014-05-14, 最終更新日: 2024-11-06)

主引用文献

Taylor, P.,Takeuchi, H.,Sheppard, D.,Chillakuri, C.,Lea, S.M.,Haltiwanger, R.S.,Handford, P.A.
Fringe-Mediated Extension of O-Linked Fucose in the Ligand-Binding Region of Notch1 Increases Binding to Mammalian Notch Ligands.
Proc.Natl.Acad.Sci.USA, 111:7290-, 2014

PubMed Abstract: The Notch signaling pathway is essential for many aspects of development, cell fate determination, and tissue homeostasis. Notch signaling can be modulated by posttranslational modifications to the Notch receptor, which are known to alter both ligand binding and receptor activation. We have modified the ligand-binding region (EGF domains 11-13) of human Notch1 (hN1) with O-fucose and O-glucose glycans and shown by flow cytometry and surface plasmon resonance that the Fringe-catalyzed addition of GlcNAc to the O-fucose at T466 in EGF12 substantially increases binding to Jagged1 and Delta-like 1 (DLL1) ligands. We have subsequently determined the crystal structures of EGF domains 11-13 of hN1 modified with either the O-fucose monosaccharide or the GlcNAc-fucose disaccharide at T466 of EGF12 and observed no change in backbone structure for each variant. Collectively, these data demonstrate a role for GlcNAc in modulating the ligand-binding site in hN1 EGF12, resulting in an increased affinity of this region for ligands Jagged1 and DLL1. We propose that this finding explains the Fringe-catalyzed enhancement of Notch-Delta signaling observed in flies and humans, but suggest that the inhibitory effect of Fringe on Jagged/Serrate mediated signaling involves other regions of Notch.

PubMed: 24803430
DOI: 10.1073/PNAS.1319683111

実験手法

X-RAY DIFFRACTION (2.29 Å)