Structural Insights into Notch Receptor-Ligand Interactions

Advances in Experimental Medicine and Biology
Penny A HandfordSusan M Lea

Abstract

Pioneering cell aggregation experiments from the Artavanis-Tsakonas group in the late 1980's localized the core ligand recognition sequence in the Drosophila Notch receptor to epidermal growth factor-like (EGF) domains 11 and 12. Since then, advances in protein expression, structure determination methods and functional assays have enabled us to define the molecular basis of the core receptor/ligand interaction and given new insights into the architecture of the Notch complex at the cell surface. We now know that Notch EGF11 and 12 interact with the Delta/Serrate/LAG-2 (DSL) and C2 domains of ligand and that membrane-binding, together with additional protein-protein interactions outside the core recognition domains, are likely to fine-tune generation of the Notch signal. Furthermore, structure determination of O-glycosylated variants of Notch alone or in complex with receptor fragments, has shown that these sugars contribute directly to the binding interface, as well as to stabilizing intra-molecular domain structure, providing some mechanistic insights into the observed modulatory effects of O-glycosylation on Notch activity.Future challenges lie in determining the complete extracellular architecture of ligand and receptor in o...Continue Reading

Citations

Mar 4, 2020·Biomolecules·Rogers Brown, Andrew K Groves
Jun 11, 2020·Glycobiology·Florian PennarubiaSébastien Legardinier
Nov 6, 2020·Oxidative Medicine and Cellular Longevity·Cheng YuanXiaoyan Wu
Jun 9, 2020·Protein Expression and Purification·Justin A GrennellMegan A Macnaughtan
Jul 25, 2021·Proceedings of the National Academy of Sciences of the United States of America·Matthieu R ZeronianBert J C Janssen
Sep 23, 2021·Disease Models & Mechanisms·Anabel Martinez Lyons, Luke Boulter

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