Spatial N-glycan rearrangement on α5β1 integrin nucleates galectin-3 oligomers to determine endocytic fate
Membrane glycoproteins frequently adopt different conformations when altering between active and inactive states. Here, we discover a molecular switch that exploits dynamic spatial rearrangements of N-glycans during such conformational transitions to control protein function. For the conformationally switchable cell adhesion glycoprotein α<sub>5</sub>β<sub>1</sub> integrin, we find that only the bent-closed state arranges N-glycans to nucleate the formation of up to tetrameric oligomers of the glycan-binding protein galectin-3. We propose a structural model of how these galectin-3 oligomers are built and how they clamp the bent-closed state to select it for endocytic uptake and subsequent retrograde trafficking to the Golgi for polarized distribution in cells. Our findings reveal the dynamic regulation of the glycan landscape at the cell surface to achieve oligomerization of galectin-3. Galectin-3 oligomers are thereby identified as functional decoders of defined spatial patterns of N-glycans on specifically the bent-closed conformational state of α<sub>5</sub>β<sub>1</sub> integrin and possibly other integrin family members.
Authors
- Siau‐Kun Bai
- Ilyes Hamitouche (ORCID: https://orcid.org/0000-0002-6920-770X)
- Daniel Lévy (ORCID: https://orcid.org/0000-0002-8949-4072)
- Christian Wunder (ORCID: https://orcid.org/0000-0001-9091-0080)
- Tia E. Keyes (ORCID: https://orcid.org/0000-0002-4604-5533)
- Agnès Hovasse (ORCID: https://orcid.org/0000-0001-5241-9688)
- Stefan Raunser (ORCID: https://orcid.org/0000-0001-9373-3016)
- J. B. D. Robinson (ORCID: https://orcid.org/0000-0002-0447-0822)
- Daniel Roderer (ORCID: https://orcid.org/0000-0002-7276-3467)
- Estelle Dransart (ORCID: https://orcid.org/0000-0003-2547-6825)
- Nirod Kumar Sarangi (ORCID: https://orcid.org/0000-0002-6914-5297)
- Raju Regmi (ORCID: https://orcid.org/0000-0003-4035-0390)
- Aurélie Di Cicco (ORCID: https://orcid.org/0000-0002-9615-7218)
- Valérie Chambon
- Massiullah Shafaq‐Zadah (ORCID: https://orcid.org/0000-0002-7582-8131)
- Ulf J. Nilsson (ORCID: https://orcid.org/0000-0001-5815-9522)
- Ludovic Leconte (ORCID: https://orcid.org/0000-0002-6917-3191)
- Sarah Cianférani (ORCID: https://orcid.org/0000-0003-4013-4129)
- Cesar Augusto Valades‐Cruz (ORCID: https://orcid.org/0000-0002-1786-8207)
- Ludger Johannes (ORCID: https://orcid.org/0000-0002-2168-0004)
- Hakon Leffler (ORCID: https://orcid.org/0000-0003-4482-8945)
- Richard Bartels
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Lund University (SE)
- Chinese Academy of Sciences (CN)
- Université Paris Sciences et Lettres (FR)
- Institute of Hydrobiology (CN)
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- Max Planck Institute of Molecular Physiology (DE)
- Centre Inria de l'Université de Rennes (FR)
- National Computational Infrastructure (AU)
- Biologie cellulaire et Cancer (FR)
- Dublin City University (IE)
- Université de Strasbourg (FR)
- Institut Curie (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-27
- DOI
- https://doi.org/10.1038/s41467-025-64523-7
- Citations
- 4
- Primary Topic
- Galectins and Cancer Biology
- Type
- article
- Field-Weighted Citation Impact
- 3.19
Funders
- Mizutani Foundation for Glycoscience
- Infrastructures en Biologie Santé et Agronomie
- Galecto
- European Commission
- Science Foundation Ireland
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Centre National de la Recherche Scientifique
- Freie Universität Berlin
- Institut Gustave-Roussy