Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP.
The neural cell adhesion molecule (NCAM) promotes axonal outgrowth, presumably through an interaction with the fibroblast growth factor receptor (FGFR). NCAM also has a little-understood ATPase activity. We here demonstrate for the first time a direct interaction between NCAM (fibronectin type III [F3] modules 1 and 2) and FGFR1 (Ig modules 2 and 3) by surface plasmon resonance (SPR) analysis. The structure of the NCAM F3 module 2 was determined by NMR and the module was shown by NMR to interact with the FGFR1 Ig module 3 and ATP. The NCAM sites binding to FGFR and ATP were found to overlap and ATP was shown by SPR to inhibit the NCAM-FGFR binding, indicating that ATP probably regulates the NCAM-FGFR interaction. Furthermore, we demonstrate that the NCAM module was able to induce activation (phosphorylation) of FGFR and to stimulate neurite outgrowth. In contrast, ATP inhibited neurite outgrowth induced by the module.
Kiselyov
Vladislav V
VV
Protein Laboratory, Institute of Molecular Pathology, Blegdamsvej 3, Copenhagen, Denmark.
Skladchikova
Galina
G
Hinsby
Anders M
AM
Jensen
Peter Holme
PH
Kulahin
Nikolaj
N
Soroka
Vladislav
V
Pedersen
Nina
N
Tsetlin
Victor
V
Poulsen
Flemming M
FM
Berezin
Vladimir
V
Bock
Elisabeth
E
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry* / Q000378:metabolism*
D019006:Neural Cell Adhesion Molecules; D010455:Peptides; D017468:Receptors, Fibroblast Growth Factor; D000255:Adenosine Triphosphate; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; C496350:Fgfr1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1