Structural basis for Notch1 engagement of Delta-like 4
Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL)
The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1- DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation
Notch1 epidermal growth factor-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/ Lag-2 ( DSL ) domain and module at the N-terminus of Notch ligands (MNNL) domains , respectively
Threonine and serine residues on Notch1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4
The elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites , Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways