title: Disruption of the low affinity receptor-binding site in NGF allows neuronal survival and differentiation by binding to the trk gene product.
abstract: Nerve growth factor (NGF), like many other growth factors and hormones, binds to two different receptor molecules on responsive cells. The product of the proto-oncogene trk, p140trk, is a tyrosine kinase receptor that has been identified as a signal-transducing receptor for NGF, while the role of the low affinity NGF receptor, p75NGFR, in signal transduction is less clear. The crystal structure of NGF has recently been determined, although structures involved in receptor binding and biological activity are unknown. Here we show that Lys-32, Lys-34, and Lys-95 form a positively charged interface involved in binding to p75NGFR. Simultaneous modification of Lys-32 with either of the two other lysines resulted in loss of binding to p75NGFR. Despite the lack of binding to p75NGFR, these mutants retained binding to p140trk and biological activity, demonstrating a functional dissociation between the two NGF receptors.
authors.affiliation: Department of Medical Chemistry, Karolinska Institute, Stockholm, Sweden.
authors.forename: C F
authors.initials: CF
authors.lastname: Ibáñez
authors.forename: T
authors.initials: T
authors.lastname: Ebendal
authors.forename: G
authors.initials: G
authors.lastname: Barbany
authors.forename: J
authors.initials: J
authors.lastname: Murray-Rust
authors.forename: T L
authors.initials: TL
authors.lastname: Blundell
authors.forename: H
authors.initials: H
authors.lastname: Persson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009414:Nerve Growth Factors / Q000737:chemistry / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D020917:Receptor, trkA; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor; D015398:Signal Transduction
chemical_list: D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D020917:Receptor, trkA