Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
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
_version_ 1783331100552069120
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
work_keys_str_mv AT rasmussenkimkrighaar ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT falkesgaardmariahansen ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT winthermalene ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT roednikolajkulahin ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT quistgaardchristinelouise ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT teisenmarienygaard ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT edslevsofiemarie ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT petersendavidleander ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT aljubouriali ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT christensenclaus ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT thulstruppeterwaaben ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT loleggioleila ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT teilumkaare ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor
AT walmodpeterschledermann ncam2fibronectintypeiiidomainsformarigidstructurethatbindsandactivatesthefibroblastgrowthfactorreceptor