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Human NOTCH1 receptor contains 36 epidermal growth factor (EGF)-like repeating domains, in which O-glycosylation status of EGF12 domain regulates the interaction with Notch ligands. Our interest is focused on the effect of specific O-glycosylation states on the structural behavior of EGF11 and EGF10, because they appeared to affect molecular mechanism in receptor-ligand interactions by inducing some conformational alterations in these domains and/or the regions connecting two domains. To understand the structural impact of various O-glycosylation patterns on the pivotal EGF-like repeats 10, 11, and 12, we performed chemical synthesis and NMR studies of site-specifically O-glycosylated EGF11 and EGF10. Our strategy enabled us to synthesize four EGF11 and five EGF10 modules. The specific O-glycosylation states affected in vitro folding of EGF10 more than EGF11, while calcium ion had a larger effect on EGF11 folding. Comprehensive NMR studies shed light on the new type "sugar bridges" crosslinking Thr-O-GlcNAc in the consensus sequence C5-X-X-G-X-(T/S)-G-X-X-C6 and an amino acid in the hinge region between the domains, 445Thr-O-GlcNAc-IIe451 in domain 11 and 405Thr-O-GlcNAc-Gln411 in domain 10, respectively. © 2020 Wiley-VCH GmbH.

Citation

Yasuhiro Yokoi, Shin-Ichiro Nishimura. Effect of Site-Specific O-Glycosylation on the Structural Behavior of NOTCH1 Receptor Extracellular EGF-like Domains 11 and 10. Chemistry (Weinheim an der Bergstrasse, Germany). 2020 Sep 25;26(54):12363-12372

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PMID: 32632967

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