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

Shafaq-Zadah, Massiullah ; Dransart, Estelle ; Hamitouche, Ilyes ; Wunder, Christian ; Chambon, Valérie ; Valades-Cruz, Cesar A. ; Leconte, Ludovic ; Sarangi, Nirod Kumar ; Robinson, Jack and Bai, Siau-Kun , et al. (2025) In Nature Communications 16.
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Polysaccharides/metabolism, Integrin alpha5beta1/metabolism, Galectin 3/metabolism, Humans, Endocytosis, Protein Conformation, Protein Multimerization, Golgi Apparatus/metabolism, Animals, Models, Molecular, Blood Proteins, Galectins
in
Nature Communications
volume
16
article number
9461
pages
29 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:41145507
  • scopus:105019753826
ISSN
2041-1723
DOI
10.1038/s41467-025-64523-7
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
b4af77df-f4b3-48a6-a098-f1f2c307d0dd
date added to LUP
2025-10-30 19:15:04
date last changed
2025-10-31 13:52:38
@article{b4af77df-f4b3-48a6-a098-f1f2c307d0dd,
  abstract     = {{Membrane glycoproteins frequently adopt different conformations when <br>
altering between active and inactive states. Here, we discover a <br>
molecular switch that exploits dynamic spatial rearrangements of <br>
N-glycans during such conformational transitions to control protein <br>
function. For the conformationally switchable cell adhesion glycoprotein<br>
 α<sub>5</sub>β<sub>1</sub> integrin, we find that only the bent-closed <br>
state arranges N-glycans to nucleate the formation of up to tetrameric <br>
oligomers of the glycan-binding protein galectin-3. We propose a <br>
structural model of how these galectin-3 oligomers are built and how <br>
they clamp the bent-closed state to select it for endocytic uptake and <br>
subsequent retrograde trafficking to the Golgi for polarized <br>
distribution in cells. Our findings reveal the dynamic regulation of the<br>
 glycan landscape at the cell surface to achieve oligomerization of <br>
galectin-3. Galectin-3 oligomers are thereby identified as functional <br>
decoders of defined spatial patterns of N-glycans on specifically the <br>
bent-closed conformational state of α<sub>5</sub>β<sub>1</sub> integrin and possibly other integrin family members.}},
  author       = {{Shafaq-Zadah, Massiullah and Dransart, Estelle and Hamitouche, Ilyes and Wunder, Christian and Chambon, Valérie and Valades-Cruz, Cesar A. and Leconte, Ludovic and Sarangi, Nirod Kumar and Robinson, Jack and Bai, Siau-Kun and Regmi, Raju and Di Cicco, Aurélie and Hovasse, Agnès and Bartels, Richard and Nilsson, Ulf J. and Cianférani-Sanglier, Sarah and Leffler, Hakon and Keyes, Tia E. and Lévy, Daniel and Raunser, Stefan and Roderer, Daniel and Johannes, Ludger}},
  issn         = {{2041-1723}},
  keywords     = {{Polysaccharides/metabolism; Integrin alpha5beta1/metabolism; Galectin 3/metabolism; Humans; Endocytosis; Protein Conformation; Protein Multimerization; Golgi Apparatus/metabolism; Animals; Models, Molecular; Blood Proteins; Galectins}},
  language     = {{eng}},
  month        = {{10}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Spatial N-glycan rearrangement on α<sub>5</sub>β<sub>1</sub> integrin nucleates galectin-3 oligomers to determine endocytic fate}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-64523-7}},
  doi          = {{10.1038/s41467-025-64523-7}},
  volume       = {{16}},
  year         = {{2025}},
}