title: Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors.
abstract: Nerve growth factor engages two structurally distinct transmembrane receptors, TrkA and p75, which have been proposed to create a "high-affinity" NGF binding site through formation of a ternary TrkA/NGF/p75 complex. To define a structural basis for the high-affinity site, we have determined the three-dimensional structure of a complete extracellular domain of TrkA complexed with NGF. The complex reveals a crab-shaped homodimeric TrkA structure, but a mechanism for p75 coordination is not obvious. We investigated the heterodimerization of membrane-bound TrkA and p75, on intact mammalian cells, using a beta-gal protein-protein interaction system. We find that NGF dimerizes TrkA and that p75 exists on the cell surface as a preformed oligomer that is not dissociated by NGF. We find no evidence for a direct TrkA/p75 interaction. We propose that TrkA and p75 likely communicate through convergence of downstream signaling pathways and/or shared adaptor molecules, rather than through direct extracellular interactions.
authors.affiliation: Baxter Laboratory for Genetic Pharmacology, Department of Microbiology and Immunology, The Stem Cell Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Wehrman
authors.forename: Xiaolin
authors.initials: X
authors.lastname: He
authors.forename: Bill
authors.initials: B
authors.lastname: Raab
authors.forename: Abhiram
authors.initials: A
authors.lastname: Dukipatti
authors.forename: Helen
authors.initials: H
authors.lastname: Blau
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D019281:Dimerization; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D008024:Ligands; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D020932:Nerve Growth Factor / Q000737:chemistry* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D017434:Protein Structure, Tertiary / Q000502:physiology; D020800:Receptor, Nerve Growth Factor / Q000737:chemistry* / Q000378:metabolism; D020917:Receptor, trkA / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D008024:Ligands; D046911:Macromolecular Substances; D020800:Receptor, Nerve Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA