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Structural and functional dissection of the interplay between lipid and Notch binding by human Notch ligands

DOI: 10.15252/embj.201796632 DOI Help

Authors: Richard J. Suckling (University of Oxford) , Boguslawa Korona (University of Oxford) , Pat Whiteman (University of Oxford) , Chandramouli Chillakuri (University of Oxford) , Laurie Holt (University of Oxford) , Penny A. Handford (University of Oxford) , Susan M. Lea (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal

State: Published (Approved)
Published: June 2017
Diamond Proposal Number(s): 12346

Open Access Open Access

Abstract: Recent data have expanded our understanding of Notch signalling by identifying a C2 domain at the N‐terminus of Notch ligands, which has both lipid‐ and receptor‐binding properties. We present novel structures of human ligands Jagged2 and Delta‐like4 and human Notch2, together with functional assays, which suggest that ligand‐mediated coupling of membrane recognition and Notch binding is likely to be critical in establishing the optimal context for Notch signalling. Comparisons between the Jagged and Delta family show a huge diversity in the structures of the loops at the apex of the C2 domain implicated in membrane recognition and Jagged1 missense mutations, which affect these loops and are associated with extrahepatic biliary atresia, lead to a loss of membrane recognition, but do not alter Notch binding. Taken together, these data suggest that C2 domain binding to membranes is an important element in tuning ligand‐dependent Notch signalling in different physiological contexts.

Journal Keywords: Delta‐like; Jagged; lipid‐binding; Notch; specificity

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 08/06/2017 15:26

Documents:
embj.201796632.full.pdf

Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)