Structural basis for Notch1 engagement of Delta-like 4

Luca, Vincent C.; Jude, Kevin M.; Pierce, Nathan W.; Nachury, Maxence V.; Fischer, Suzanne; Garcia, K. Christopher

doi:10.1126/science.1261093

Title: Structural basis for Notch1 engagement of Delta-like 4

Journal Article · Fri Feb 20 00:00:00 EST 2015 · Science

DOI:https://doi.org/10.1126/science.1261093· OSTI ID:1182315

Luca, Vincent C. ^[1]; Jude, Kevin M. ^[1]; Pierce, Nathan W. ^[2]; Nachury, Maxence V. ^[2]; Fischer, Suzanne ^[1]; Garcia, K. Christopher ^[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
Stanford Univ. School of Medicine, Stanford, CA (United States). Dept. of Molecular and Cellular Physiology

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-76SF00515; NIH-1RO1-GM097015

OSTI ID:: 1182315

Journal Information:: Science, Vol. 347, Issue 6224; ISSN 0036-8075

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 181 works

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Biological functions of fucose in mammals Schneider, Michael; Al-Shareffi, Esam; Haltiwanger, Robert S. Glycobiology, Vol. 27, Issue 7 https://doi.org/10.1093/glycob/cwx034	journal	May 2017
Cis-activation in the Notch signaling pathway Nandagopal, Nagarajan; Santat, Leah A.; Elowitz, Michael B. eLife, Vol. 8 https://doi.org/10.7554/elife.37880	journal	January 2019

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