RT Journal Article
SR Electronic
T1 Structural and functional dissection of the interplay between lipid and Notch binding by human Notch ligands
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 101394
DO 10.1101/101394
A1 Richard J. Suckling
A1 Boguslawa Korona
A1 Patricia Whiteman
A1 Chandramouli Chillakuri
A1 Laurie Holt
A1 Penny A. Handford
A1 Susan M. Lea
YR 2017
UL http://biorxiv.org/content/early/2017/01/18/101394.abstract
AB Recent data have expanded our understanding of Notch signaling 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 DLL4 and human Notch-2, 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 signaling. 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 signaling in different physiological contexts.