A cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates

Sébastien Cardon, Yadira P. Hervis, Gérard Bolbach, Chrystel Lopin-Bon, Jean-Claude Jacquinet, Françoise Illien, Astrid Walrant, Delphine Ravault, Bingwei He, Laura Molina, Fabienne Burlina, Olivier Lequin, Alain Joliot, Ludovic Carlier () and Sandrine Sagan ()
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Sébastien Cardon: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)
Yadira P. Hervis: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)
Gérard Bolbach: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)
Chrystel Lopin-Bon: Univ. Orléans, CNRS, ICOA
Jean-Claude Jacquinet: Univ. Orléans, CNRS, ICOA
Françoise Illien: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)
Astrid Walrant: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)
Delphine Ravault: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)
Bingwei He: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)
Laura Molina: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)
Fabienne Burlina: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)
Olivier Lequin: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)
Alain Joliot: PSL Research University
Ludovic Carlier: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)
Sandrine Sagan: Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Engrailed2 (En2) is a transcription factor that transfers from cell to cell through unconventional pathways. The poorly understood internalization mechanism of this cationic protein is proposed to require an initial interaction with cell-surface glycosaminoglycans (GAGs). To decipher the role of GAGs in En2 internalization, we have quantified the entry of its homeodomain region in model cells that differ in their content in cell-surface GAGs. The binding specificity to GAGs and the influence of this interaction on the structure and dynamics of En2 was also investigated at the amino acid level. Our results show that a high-affinity GAG-binding sequence (RKPKKKNPNKEDKRPR), upstream of the homeodomain, controls En2 internalization through selective interactions with highly-sulfated heparan sulfate GAGs. Our data underline the functional importance of the intrinsically disordered basic region upstream of En2 internalization domain, and demonstrate the critical role of GAGs as an entry gate, finely tuning homeoprotein capacity to internalize into cells.

Date: 2023
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DOI: 10.1038/s41467-023-37757-6

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