NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor

Abstract 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...

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Autores principales:	Kim Krighaar Rasmussen, Maria Hansen Falkesgaard, Malene Winther, Nikolaj Kulahin Roed, Christine Louise Quistgaard, Marie Nygaard Teisen, Sofie Marie Edslev, David Leander Petersen, Ali Aljubouri, Claus Christensen, Peter Waaben Thulstrup, Leila Lo Leggio, Kaare Teilum, Peter Schledermann Walmod
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0d20311e21774d27b2f15fe4f66a9f48
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spelling	oai:doaj.org-article:0d20311e21774d27b2f15fe4f66a9f482021-12-02T15:08:17ZNCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor10.1038/s41598-018-27089-72045-2322https://doaj.org/article/0d20311e21774d27b2f15fe4f66a9f482018-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-27089-7https://doaj.org/toc/2045-2322Abstract 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.Kim Krighaar RasmussenMaria Hansen FalkesgaardMalene WintherNikolaj Kulahin RoedChristine Louise QuistgaardMarie Nygaard TeisenSofie Marie EdslevDavid Leander PetersenAli AljubouriClaus ChristensenPeter Waaben ThulstrupLeila Lo LeggioKaare TeilumPeter Schledermann WalmodNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kim Krighaar Rasmussen Maria Hansen Falkesgaard Malene Winther Nikolaj Kulahin Roed Christine Louise Quistgaard Marie Nygaard Teisen Sofie Marie Edslev David Leander Petersen Ali Aljubouri Claus Christensen Peter Waaben Thulstrup Leila Lo Leggio Kaare Teilum Peter Schledermann Walmod NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor
description	Abstract 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	article
author	Kim Krighaar Rasmussen Maria Hansen Falkesgaard Malene Winther Nikolaj Kulahin Roed Christine Louise Quistgaard Marie Nygaard Teisen Sofie Marie Edslev David Leander Petersen Ali Aljubouri Claus Christensen Peter Waaben Thulstrup Leila Lo Leggio Kaare Teilum Peter Schledermann Walmod
author_facet	Kim Krighaar Rasmussen Maria Hansen Falkesgaard Malene Winther Nikolaj Kulahin Roed Christine Louise Quistgaard Marie Nygaard Teisen Sofie Marie Edslev David Leander Petersen Ali Aljubouri Claus Christensen Peter Waaben Thulstrup Leila Lo Leggio Kaare Teilum Peter Schledermann Walmod
author_sort	Kim Krighaar Rasmussen
title	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_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_sort	ncam2 fibronectin type-iii domains form a rigid structure that binds and activates the fibroblast growth factor receptor
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/0d20311e21774d27b2f15fe4f66a9f48
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NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor

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