A cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates
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 ro...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37757-6 |
| _version_ | 1797845900403408896 |
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| author | 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 Sandrine Sagan |
| author_facet | 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 Sandrine Sagan |
| author_sort | Sébastien Cardon |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T17:46:27Z |
| format | Article |
| id | doaj.art-c684e2cdb0ba43a69d9c0fdf51449845 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T17:46:27Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-c684e2cdb0ba43a69d9c0fdf514498452023-04-16T11:18:16ZengNature PortfolioNature Communications2041-17232023-04-0114111310.1038/s41467-023-37757-6A cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfatesSébastien Cardon0Yadira P. Hervis1Gérard Bolbach2Chrystel Lopin-Bon3Jean-Claude Jacquinet4Françoise Illien5Astrid Walrant6Delphine Ravault7Bingwei He8Laura Molina9Fabienne Burlina10Olivier Lequin11Alain Joliot12Ludovic Carlier13Sandrine Sagan14Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)Univ. Orléans, CNRS, ICOAUniv. Orléans, CNRS, ICOASorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)INSERM U932, Institut Curie Centre de Recherche, PSL Research UniversitySorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM)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.https://doi.org/10.1038/s41467-023-37757-6 |
| spellingShingle | 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 Sandrine Sagan A cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates Nature Communications |
| title | A cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates |
| title_full | A cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates |
| title_fullStr | A cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates |
| title_full_unstemmed | A cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates |
| title_short | A cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates |
| title_sort | cationic motif upstream engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates |
| url | https://doi.org/10.1038/s41467-023-37757-6 |
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