PDBsum entry 4d0f

Transcription

PDB id: 4d0f

Contents

Protein chain

125 a.a.

Ligands

EDO

Metals

_CA ×3

Waters ×13

PDB id:

4d0f

Name:

Transcription

Title:

Human notch1 egf domains 11-13 mutant t466a

Structure:

Neurogenic locus notch homolog protein 1. Chain: a. Fragment: egf 11-13. Synonym: notch 1, hn1, translocation-associated notch protein tan-1, human notch. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.80Å R-factor: 0.225 R-free: 0.265

Authors:

P.Taylor,H.Takeuchi,D.Sheppard,C.Chillakuri,S.M.Lea,R.S.Haltiwanger, P.A.Handford

Key ref:

P.Taylor et al. (2014). Fringe-mediated extension of O-linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands. Proc Natl Acad Sci U S A, 111, 7290-7295. PubMed id: 24803430 DOI: 10.1073/pnas.1319683111

Date:

25-Apr-14 Release date: 21-May-14

Protein chain

P46531  (NOTC1_HUMAN) -  Neurogenic locus notch homolog protein 1 from Homo sapiens

Seq: 2555 a.a.

Struc: 125 a.a.*

* PDB and UniProt seqs differ at 9 residue positions (black crosses)

DOI no: 10.1073/pnas.1319683111

Proc Natl Acad Sci U S A 111:7290-7295 (2014)

PubMed id: 24803430

Fringe-mediated extension of O-linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands.

P.Taylor, H.Takeuchi, D.Sheppard, C.Chillakuri, S.M.Lea, R.S.Haltiwanger, P.A.Handford.

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.