AN IMMUNOGLOBULIN-LIKE DOMAIN DETERMINES THE SPECIFICITY OF NEUROTROPHIN RECEPTORS

The neurotrophins influence survival and maintenance of vertebrate neu rons in the embryonic, early postnatal and post-developmental stages o f 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 t rkC with neurotrophin-3 (NT-3), By constructing 17 different chimeras and domain deletions of the human trk receptors and analyzing their bi nding affinities to the neurotrophins we have shown that an immunoglob ulin-like domain located adjacent to the transmembrane domain is the s tructural element that determines the interaction of neurotrophins wit h their receptors. Chimeras of trkC where this domain was exchanged fo r the homologous sequences from trkB or trkA gained high affinity bind ing to BDNF or NGF respectively, while deletion of this domain in trkC or trkA abolished binding to NT-3 or NGF respectively, This domain al one retained affinities to neurotrophins similar to the full-length re ceptors and when expressed on NIH 3T3 cells in fusion with the kinase domain showed neurotrophin-dependent activation.