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Peer-reviewedCC BY-NC-ND 4.0JACS Au

Glycosylation Encodes Selective Galectin Recognition and Signaling by Osteopontin

  • Iris A. Bermejo1
  • Diego Del Balzo1
  • Mikel Azkargorta1
  • Alberto Marina1
  • Sandra Delgado1
  • Ana Gimeno1,2
  • Francesca Peccati1,2
  • Tammo Diercks1
  • Félix Elortza1
  • Oscar Millet1
  • Ana Ardá1,2
  • Borja Mateos3
2 more authors
  • Jesús Jiménez-Barbero1,2,4,5
  • Luca Unione1,2
5 affiliations
  1. 1Center for Cooperative Research in Biosciences (CIC bioGUNE) , ,
  2. 2Ikerbasque, Basque Foundation for Science , ,
  3. 3University of Barcelona , , Martí i Franquès 1-11 , ,
  4. 4University of the Basque Country, EHU , , ,
  5. 5Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias , ,
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Abstract

Post-translational modifications critically regulate extracellular molecular recognition, yet their roles in intrinsically disordered proteins remain poorly defined. Here, we integrate glycoproteomics, NMR, and cellular assays to reveal how glycosylation shapes the interaction network of osteopontin (OPN), a highly glycosylated intrinsically disordered protein. We show that OPN displays a heterogeneous repertoire of predominantly sialylated O-glycans that drive selective lectin binding: galectin-3 preferentially binds terminal LacNAc-containing epitopes, whereas galectin-8 engages multiple sialylated and sulfated glycan motifs, promoting cross-linking of OPN. In contrast, binding to CD44 receptor is largely glycosylation-independent and is mediated primarily through the polypeptide backbone. This dual recognition mechanism enables OPN to act as a molecular scaffold that couples glycan-mediated galectin binding with CD44 receptor engagement. Consistent with this proposed mechanistic model, OPN/galectin complexes are recruited to CD44-expressing cells where glycosylated OPN suppresses galectin-8-induced apoptosis, whereas deglycosylated OPN does not. Together, our results reveal that glycosylation encodes interaction specificity and downstream signaling outcomes in an intrinsically disordered extracellular protein, establishing OPN as a paradigm for how glycans organize extracellular recognition networks.

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Cite

BibTeXRIS
BibTeX
@article{bermejo2026glycosylation,
  title = {{Glycosylation Encodes Selective Galectin Recognition and Signaling by Osteopontin}},
  author = {Iris A. Bermejo and Diego Del Balzo and Mikel Azkargorta and Alberto Marina and Sandra Delgado and Ana Gimeno and Francesca Peccati and Tammo Diercks and Félix Elortza and Oscar Millet and Ana Ardá and Borja Mateos and Jesús Jiménez-Barbero and Luca Unione},
  journal = {JACS Au},
  year = {2026},
  month = oct,
  doi = {10.1021/jacsau.6c01041},
  url = {https://pubs.acs.org/jaaucr/article/6/10/5744/5443615/Glycosylation-Encodes-Selective-Galectin},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Glycosylation Encodes Selective Galectin Recognition and Signaling by Osteopontin
AU  - Iris A. Bermejo
AU  - Diego Del Balzo
AU  - Mikel Azkargorta
AU  - Alberto Marina
AU  - Sandra Delgado
AU  - Ana Gimeno
AU  - Francesca Peccati
AU  - Tammo Diercks
AU  - Félix Elortza
AU  - Oscar Millet
AU  - Ana Ardá
AU  - Borja Mateos
AU  - Jesús Jiménez-Barbero
AU  - Luca Unione
PY  - 2026
DA  - 2026/10/01
JO  - JACS Au
DO  - 10.1021/jacsau.6c01041
UR  - https://pubs.acs.org/jaaucr/article/6/10/5744/5443615/Glycosylation-Encodes-Selective-Galectin
AB  - Post-translational modifications critically regulate extracellular molecular recognition, yet their roles in intrinsically disordered proteins remain poorly defined. Here, we integrate glycoproteomics, NMR, and cellular assays to reveal how glycosylation shapes the interaction network of osteopontin (OPN), a highly glycosylated intrinsically disordered protein. We show that OPN displays a heterogeneous repertoire of predominantly sialylated O-glycans that drive selective lectin binding: galectin-3 preferentially binds terminal LacNAc-containing epitopes, whereas galectin-8 engages multiple sialylated and sulfated glycan motifs, promoting cross-linking of OPN. In contrast, binding to CD44 receptor is largely glycosylation-independent and is mediated primarily through the polypeptide backbone. This dual recognition mechanism enables OPN to act as a molecular scaffold that couples glycan-mediated galectin binding with CD44 receptor engagement. Consistent with this proposed mechanistic model, OPN/galectin complexes are recruited to CD44-expressing cells where glycosylated OPN suppresses galectin-8-induced apoptosis, whereas deglycosylated OPN does not. Together, our results reveal that glycosylation encodes interaction specificity and downstream signaling outcomes in an intrinsically disordered extracellular protein, establishing OPN as a paradigm for how glycans organize extracellular recognition networks.
SN  - 2691-3704
ER  -