N-Sulfated Heparan Sulfate Promotes Reelin Signaling as a Co-receptor

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Heparan sulfate (HS) plays a central role in signal transduction, while Reelin is an essential signaling protein in both the developing and adult brain. A Reelin COLBOS variant was recently discovered with enhanced HS binding and resilience against autosomal dominant Alzheimer’s disease (ADAD), underscoring the importance of Reelin–HS interactions. However, the glycan determinants of Reelin–HS interactions have not been well-characterized, which we systematically investigated here. Surface plasmon resonance (SPR) showed that full length Reelin binds HS with high affinity ( K D = 17 ± 5 nM), which is enhanced by the COLBOS variant ( K D = 10 ± 2 nM). Competition SPR and glycan array studies further revealed that HS N-sulfation is critical for Reelin–HS binding, consistent with Haddock modeling. In cell surface binding assays, heparinase treatment, which degrades HS, or the knockout of a key HS N-sulfation enzyme (NDST1) significantly reduced Reelin attachment. Functionally, a cellular split-luciferase assay showed that heparinase treatment or adding heparin in culture medium reduces Reelin-induced ApoER2 dimerization, demonstrating that HS is a coreceptor for Reelin receptor activation. In contrast, N-desulfated heparin does not inhibit Reelin receptor dimerization. Our work establishes HS as a coreceptor for Reelin signaling and N-sulfation as a key glycan determinant of Reelin–HS recognition. Our work provides mechanistic insights into diverse neurodevelopmental and neurodegenerative diseases associated with Reelin signaling and suggests novel therapeutic strategies targeting HS sulfation.

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