Apr 7, 2014

N-glycosylation blocks and simultaneously fosters different receptor-ligand binding sites: the chameleonic CD44-hyaluronan interaction

BioRxiv : the Preprint Server for Biology
Matthew PennellHector Martinez-Seara


While protein function is largely encoded in DNA, it is also modulated by a complementary and often invisible layer of information encoded by glycans attached to the protein surface. The CD44-hyaluronan complex involved in inflammatory responses and cell migration is a prime example of the significance of glycans, as the ability of the cell surface receptor CD44 to bind its ligand, hyaluronan, is modulated by N-glycosylation. Intriguingly, how glycans can regulate this binding process, and the activation of CD44, has remained unclear. In this work, 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. While non-glycosylated CD44 is found to favor the canonical sub-micromolar binding site, 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 constitutes a challenge for protein structure determinatio...Continue Reading

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