N-Glycosylation can selectively block or foster different receptor–ligand binding modes

Joni Vuorio, Jana Škerlová, Milan Fábry, Václav Veverka, Ilpo Vattulainen, Pavlína Řezáčová, Hector Martinez-Seara

Research output: Contribution to journalArticleScientificpeer-review

Abstract

While DNA encodes protein structure, glycans provide a complementary layer of information to protein function. As a prime example of the significance of glycans, the ability of the cell surface receptor CD44 to bind its ligand, hyaluronan, is modulated by N-glycosylation. However, the details of this modulation remain unclear. Based on atomistic simulations and NMR, we provide evidence that CD44 has multiple distinct binding sites for hyaluronan, and that N-glycosylation modulates their respective roles. We find that non-glycosylated CD44 favors the canonical sub-micromolar binding site, while glycosylated CD44 binds hyaluronan with an entirely different micromolar binding site. Our findings show (for the first time) how glycosylation can alter receptor affinity by shielding specific regions of the host protein, thereby promoting weaker binding modes. The mechanism revealed in this work emphasizes the importance of glycosylation in protein function and poses a challenge for protein structure determination where glycosylation is usually neglected.

Original languageEnglish
Article number5239
Number of pages12
JournalScientific Reports
Volume11
Issue number1
DOIs
Publication statusPublished - 2021
Publication typeA1 Journal article-refereed

Publication forum classification

  • Publication forum level 1

ASJC Scopus subject areas

  • General

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