Spatial N-glycan rearrangement on α5β1 integrin nucleates galectin-3 oligomers to determine endocytic fate

Massiullah Shafaq-Zadah (), Estelle Dransart, Ilyes Hamitouche, Christian Wunder, Valérie Chambon, Cesar A. Valades-Cruz, Ludovic Leconte, Nirod Kumar Sarangi, Jack Robinson, Siau-Kun Bai, Raju Regmi, Aurélie Cicco, Agnès Hovasse, Richard Bartels, Ulf J. Nilsson, Sarah Cianférani-Sanglier, Hakon Leffler, Tia E. Keyes, Daniel Levy (), Stefan Raunser, Daniel Roderer () and Ludger Johannes ()
Additional contact information
Massiullah Shafaq-Zadah: PSL Research University
Estelle Dransart: PSL Research University
Ilyes Hamitouche: PSL Research University
Christian Wunder: PSL Research University
Valérie Chambon: PSL Research University
Cesar A. Valades-Cruz: PSL Research University
Ludovic Leconte: PSL Research University
Nirod Kumar Sarangi: Dublin City University
Jack Robinson: Dublin City University
Siau-Kun Bai: PSL Research University
Raju Regmi: PSL Research University
Aurélie Cicco: PSL Research University
Agnès Hovasse: Strasbourg University
Richard Bartels: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Ulf J. Nilsson: Lund University
Sarah Cianférani-Sanglier: Strasbourg University
Hakon Leffler: Lund University
Tia E. Keyes: Dublin City University
Stefan Raunser: Max Planck Institute of Molecular Physiology
Daniel Roderer: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Ludger Johannes: PSL Research University

Nature Communications, 2025, vol. 16, issue 1, 1-29

Abstract: Abstract 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 α5β1 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 α5β1 integrin and possibly other integrin family members.

Date: 2025
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DOI: 10.1038/s41467-025-64523-7

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