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Title: 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. Lastly, 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.
Authors:
 [1] ;  [1] ;  [2] ;  [2] ;  [1] ;  [1]
  1. Stanford Univ. School of Medicine, Stanford, CA (United States). Howard Hughes Medical Inst.; Stanford Univ. School of Medicine, Stanford, CA (United States). Dept. of Molecular and Cellular Physiology; Stanford Univ. School of Medicine, Stanford, CA (United States). Dept. of Structural Biology
  2. Stanford Univ. School of Medicine, Stanford, CA (United States). Dept. of Molecular and Cellular Physiology
Publication Date:
OSTI Identifier:
1182315
Grant/Contract Number:
AC02-76SF00515; NIH-1RO1-GM097015
Type:
Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 347; Journal Issue: 6224; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Health (NIH)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES