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NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor
NCAM1 and NCAM2 have ectodomains consisting of 5 Ig domains followed by 2 membrane-proximal FnIII domains. In this study we investigate and compare the structures and functions of these FnIII domains. The NCAM1 and -2 FnIII2 domains both contain a Walker A motif. In NCAM1 binding of ATP to this moti...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997747/ https://www.ncbi.nlm.nih.gov/pubmed/29895898 http://dx.doi.org/10.1038/s41598-018-27089-7 |
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author | Rasmussen, Kim Krighaar Falkesgaard, Maria Hansen Winther, Malene Roed, Nikolaj Kulahin Quistgaard, Christine Louise Teisen, Marie Nygaard Edslev, Sofie Marie Petersen, David Leander Aljubouri, Ali Christensen, Claus Thulstrup, Peter Waaben Lo Leggio, Leila Teilum, Kaare Walmod, Peter Schledermann |
author_facet | Rasmussen, Kim Krighaar Falkesgaard, Maria Hansen Winther, Malene Roed, Nikolaj Kulahin Quistgaard, Christine Louise Teisen, Marie Nygaard Edslev, Sofie Marie Petersen, David Leander Aljubouri, Ali Christensen, Claus Thulstrup, Peter Waaben Lo Leggio, Leila Teilum, Kaare Walmod, Peter Schledermann |
author_sort | Rasmussen, Kim Krighaar |
collection | PubMed |
description | NCAM1 and NCAM2 have ectodomains consisting of 5 Ig domains followed by 2 membrane-proximal FnIII domains. In this study we investigate and compare the structures and functions of these FnIII domains. The NCAM1 and -2 FnIII2 domains both contain a Walker A motif. In NCAM1 binding of ATP to this motif interferes with NCAM1 binding to FGFR. We obtained a structural model of the NCAM2 FnIII2 domain by NMR spectroscopy, and by titration with an ATP analogue we show that the NCAM2 Walker A motif does not bind ATP. Small angle X-ray scattering (SAXS) data revealed that the NCAM2 FnIII1-2 double domain exhibits a very low degree of flexibility. Moreover, recombinant NCAM2 FnIII domains bind FGFR in vitro, and the FnIII1-2 double domain induces neurite outgrowth in a concentration-dependent manner through activation of FGFR. Several synthetic NCAM1-derived peptides induce neurite outgrowth via FGFR. Only 2 of 5 peptides derived from similar regions in NCAM2 induce neurite outgrowth, but the most potent of these peptides stimulates neurite outgrowth through FGFR-dependent activation of the Ras-MAPK pathway. These results reveal that the NCAM2 FnIII domains form a rigid structure that binds and activates FGFR in a manner related to, but different from NCAM1. |
format | Online Article Text |
id | pubmed-5997747 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59977472018-06-21 NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor Rasmussen, Kim Krighaar Falkesgaard, Maria Hansen Winther, Malene Roed, Nikolaj Kulahin Quistgaard, Christine Louise Teisen, Marie Nygaard Edslev, Sofie Marie Petersen, David Leander Aljubouri, Ali Christensen, Claus Thulstrup, Peter Waaben Lo Leggio, Leila Teilum, Kaare Walmod, Peter Schledermann Sci Rep Article NCAM1 and NCAM2 have ectodomains consisting of 5 Ig domains followed by 2 membrane-proximal FnIII domains. In this study we investigate and compare the structures and functions of these FnIII domains. The NCAM1 and -2 FnIII2 domains both contain a Walker A motif. In NCAM1 binding of ATP to this motif interferes with NCAM1 binding to FGFR. We obtained a structural model of the NCAM2 FnIII2 domain by NMR spectroscopy, and by titration with an ATP analogue we show that the NCAM2 Walker A motif does not bind ATP. Small angle X-ray scattering (SAXS) data revealed that the NCAM2 FnIII1-2 double domain exhibits a very low degree of flexibility. Moreover, recombinant NCAM2 FnIII domains bind FGFR in vitro, and the FnIII1-2 double domain induces neurite outgrowth in a concentration-dependent manner through activation of FGFR. Several synthetic NCAM1-derived peptides induce neurite outgrowth via FGFR. Only 2 of 5 peptides derived from similar regions in NCAM2 induce neurite outgrowth, but the most potent of these peptides stimulates neurite outgrowth through FGFR-dependent activation of the Ras-MAPK pathway. These results reveal that the NCAM2 FnIII domains form a rigid structure that binds and activates FGFR in a manner related to, but different from NCAM1. Nature Publishing Group UK 2018-06-12 /pmc/articles/PMC5997747/ /pubmed/29895898 http://dx.doi.org/10.1038/s41598-018-27089-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Rasmussen, Kim Krighaar Falkesgaard, Maria Hansen Winther, Malene Roed, Nikolaj Kulahin Quistgaard, Christine Louise Teisen, Marie Nygaard Edslev, Sofie Marie Petersen, David Leander Aljubouri, Ali Christensen, Claus Thulstrup, Peter Waaben Lo Leggio, Leila Teilum, Kaare Walmod, Peter Schledermann NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor |
title | NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor |
title_full | NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor |
title_fullStr | NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor |
title_full_unstemmed | NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor |
title_short | NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor |
title_sort | ncam2 fibronectin type-iii domains form a rigid structure that binds and activates the fibroblast growth factor receptor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997747/ https://www.ncbi.nlm.nih.gov/pubmed/29895898 http://dx.doi.org/10.1038/s41598-018-27089-7 |
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