title: An immunoglobulin-like domain determines the specificity of neurotrophin receptors.
abstract: The neurotrophins influence survival and maintenance of vertebrate neurons in the embryonic, early post-natal and post-developmental stages of the nervous system. Binding of neurotrophins to receptors encoded by the gene family trk initiates signal transduction into the cell. trkA interacts preferably with nerve growth factor (NGF), trkB with brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) and trkC with neurotrophin-3 (NT-3). By constructing 17 different chimeras and domain deletions of the human trk receptors and analyzing their binding affinities to the neurotrophins we have shown that an immunoglobulin-like domain located adjacent to the transmembrane domain is the structural element that determines the interaction of neurotrophins with their receptors. Chimeras of trkC where this domain was exchanged for the homologous sequences from trkB or trkA gained high affinity binding to BDNF or NGF respectively, while deletion of this domain in trkC or trkA abolished binding to NT-3 or NGF respectively. This domain alone retained affinities to neurotrophins similar to the full-length receptors and when expressed on NIH 3T3 cells in fusion with the kinase domain showed neurotrophin-dependent activation.
authors.affiliation: Department of Protein Engineering, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: R
authors.initials: R
authors.lastname: Urfer
authors.forename: P
authors.initials: P
authors.lastname: Tsoulfas
authors.forename: L
authors.initials: L
authors.lastname: O'Connell
authors.forename: D L
authors.initials: DL
authors.lastname: Shelton
authors.forename: L F
authors.initials: LF
authors.lastname: Parada
authors.forename: L G
authors.initials: LG
authors.lastname: Presta
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D019208:Brain-Derived Neurotrophic Factor; D006031:Glycosylation; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020933:Neurotrophin 3; D010766:Phosphorylation; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D017384:Sequence Deletion / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007136:Immunoglobulins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins