Cell surface glycan engineering reveals that matriglycan alone can recapitulate dystroglycan binding and function

M Osman Sheikh; Chantelle J Capicciotti; Lin Liu; Jeremy Praissman; Dahai Ding; Daniel G Mead; Melinda A Brindley; Tobias Willer; Kevin P Campbell; Kelley W Moremen; Lance Wells; Geert-Jan Boons

doi:10.1038/s41467-022-31205-7

Cell surface glycan engineering reveals that matriglycan alone can recapitulate dystroglycan binding and function

M Osman Sheikh, Chantelle J Capicciotti, Lin Liu, Jeremy Praissman, Dahai Ding, Daniel G Mead, Melinda A Brindley, Tobias Willer, Kevin P Campbell, Kelley W Moremen, Lance Wells, Geert-Jan Boons

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

α-Dystroglycan (α-DG) is uniquely modified on O-mannose sites by a repeating disaccharide (-Xylα1,3-GlcAβ1,3-) 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 demonstrate 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 α-DG or O-mannosylation with matriglycans of sufficient length recovers infection with a Lassa-pseudovirus. Finally, free matriglycan in a dose and length dependent manner inhibits 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.

Original language	English
Article number	3617
Pages (from-to)	1-13
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31205-7
Publication status	Published - Dec 2022

Bibliographical note

Funding Information:
K.P.C. is an investigator of the Howard Hughes Medical Institute and L.W. is a Georgia Research Alliance Distinguished Investigator. This work was supported in part by grants from the National Institutes of Health including R01U01GM120408 and R01HL151617 (to G.J.B.), R01GM111939 (to L.W.), R01GM130915 (to K.W.M. and L.W.), R01AI139238 (to M.A.B.), and a Paul D. Wellstone Muscular Dystrophy Specialized Research Center grant (1U54NS053672 to K.P.C.). We would like to thank all the members of all involved laboratories for helpful discussions and especially Dr. Margreet Wolfert for assisting with editing and formatting of the manuscript and associated documents.

Funding Information:
K.P.C. is an investigator of the Howard Hughes Medical Institute and L.W. is a Georgia Research Alliance Distinguished Investigator. This work was supported in part by grants from the National Institutes of Health including R01U01GM120408 and R01HL151617 (to G.J.B.), R01GM111939 (to L.W.), R01GM130915 (to K.W.M. and L.W.), R01AI139238 (to M.A.B.), and a Paul D. Wellstone Muscular Dystrophy Specialized Research Center grant (1U54NS053672 to K.P.C.). We would like to thank all the members of all involved laboratories for helpful discussions and especially Dr. Margreet Wolfert for assisting with editing and formatting of the manuscript and associated documents.

Publisher Copyright:
© 2022, The Author(s).

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Sheikh, M. O., Capicciotti, C. J., Liu, L., Praissman, J., Ding, D., Mead, D. G., Brindley, M. A., Willer, T., Campbell, K. P., Moremen, K. W., Wells, L., & Boons, G.-J. (2022). Cell surface glycan engineering reveals that matriglycan alone can recapitulate dystroglycan binding and function. Nature Communications, 13(1), 1-13. Article 3617. https://doi.org/10.1038/s41467-022-31205-7

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abstract = "α-Dystroglycan (α-DG) is uniquely modified on O-mannose sites by a repeating disaccharide (-Xylα1,3-GlcAβ1,3-) 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 demonstrate 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 α-DG or O-mannosylation with matriglycans of sufficient length recovers infection with a Lassa-pseudovirus. Finally, free matriglycan in a dose and length dependent manner inhibits 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. ",

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note = "Funding Information: K.P.C. is an investigator of the Howard Hughes Medical Institute and L.W. is a Georgia Research Alliance Distinguished Investigator. This work was supported in part by grants from the National Institutes of Health including R01U01GM120408 and R01HL151617 (to G.J.B.), R01GM111939 (to L.W.), R01GM130915 (to K.W.M. and L.W.), R01AI139238 (to M.A.B.), and a Paul D. Wellstone Muscular Dystrophy Specialized Research Center grant (1U54NS053672 to K.P.C.). We would like to thank all the members of all involved laboratories for helpful discussions and especially Dr. Margreet Wolfert for assisting with editing and formatting of the manuscript and associated documents. Funding Information: K.P.C. is an investigator of the Howard Hughes Medical Institute and L.W. is a Georgia Research Alliance Distinguished Investigator. This work was supported in part by grants from the National Institutes of Health including R01U01GM120408 and R01HL151617 (to G.J.B.), R01GM111939 (to L.W.), R01GM130915 (to K.W.M. and L.W.), R01AI139238 (to M.A.B.), and a Paul D. Wellstone Muscular Dystrophy Specialized Research Center grant (1U54NS053672 to K.P.C.). We would like to thank all the members of all involved laboratories for helpful discussions and especially Dr. Margreet Wolfert for assisting with editing and formatting of the manuscript and associated documents. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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AU - Sheikh, M Osman

AU - Capicciotti, Chantelle J

AU - Liu, Lin

AU - Praissman, Jeremy

AU - Ding, Dahai

AU - Mead, Daniel G

AU - Brindley, Melinda A

AU - Willer, Tobias

AU - Campbell, Kevin P

AU - Moremen, Kelley W

AU - Wells, Lance

AU - Boons, Geert-Jan

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Cell surface glycan engineering reveals that matriglycan alone can recapitulate dystroglycan binding and function

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