Cell Surface Glycan Engineering Reveals that Matriglycan Alone can Recapitulate Dystroglycan Binding and Function

Sheikh, M. O.; Capicciotti, C. J.; Liu, L.; Praissman, J. L.; Mead, D. G.; Brindley, M. A.; Willer, T.; Campbell, K. P.; Moremen, K. W.; Wells, L.; Boons, G.-J.

doi:10.1101/2021.05.10.443358

bioRxiv · 10.1101/2021.05.10.443358

Cell Surface Glycan Engineering Reveals that Matriglycan Alone can Recapitulate Dystroglycan Binding and Function

Sheikh, M. O.·Capicciotti, C. J.·Liu, L.·Praissman, J. L.·Mead, D. G.·Brindley, M. A.·Willer, T.·Campbell, K. P.·Moremen, K. W.·Wells, L.·Boons, G.-J.

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Abstract

-Dystroglycan (-DG) is uniquely modified on O-mannose sites by a repeating disaccharide (-Xyl1,3-GlcA{beta}1,3-)n termed matriglycan, which is a receptor for laminin-G domain-containing proteins and employed by old-world arenaviruses for infection. Using chemoenzymatically synthesized matriglycans printed as a microarray, we demonstrated length-dependent binding to Laminin, Lassa virus GP1, and the clinically-important antibody IIH6. Utilizing an enzymatic engineering approach, an N-linked glycoprotein was converted into a IIH6-positive Laminin-binding glycoprotein. Engineering of the surface of cells deficient for either -DG or O-mannosylation with matriglycans of sufficient length recovered infection with a Lassa-pseudovirus. Finally free matriglycan in a dose and length dependent manner inhibited viral infection of wildtype cells. These results indicate that matriglycan alone is necessary and sufficient for IIH6 staining, Laminin and LASV GP1 binding, and Lassa-pseudovirus infection and support a model in which it is a tunable receptor for which increasing chain length enhances ligand-binding capacity. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY Graphical Abstract C_FIG_DISPLAY

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Sheikh, M. O., Capicciotti, C. J., Liu, L., Praissman, J. L., Mead, D. G., Brindley, M. A., Willer, T., Campbell, K. P., Moremen, K. W., Wells, L., Boons, G.-J.. 2021-05-10. Cell Surface Glycan Engineering Reveals that Matriglycan Alone can Recapitulate Dystroglycan Binding and Function. https://doi.org/10.1101/2021.05.10.443358

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