Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors.
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.
Wehrman
Tom
T
Baxter Laboratory for Genetic Pharmacology, Department of Microbiology and Immunology, The Stem Cell Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
He
Xiaolin
X
Raab
Bill
B
Dukipatti
Abhiram
A
Blau
Helen
H
Garcia
K Christopher
KC
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
D008024:Ligands; D046911:Macromolecular Substances; D020800:Receptor, Nerve Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA