title: Structural model for p75(NTR)-TrkA intracellular domain interaction: a combined FRET and bioinformatics study.
abstract: Nerve growth factor (NGF) is a member of the neurotrophins, which are important regulators of embryonic development and adult function in the vertebrate nervous systems. The signaling elicited by NGF regulates diverse activities, including survival, axon growth, and synaptic plasticity. NGF action is mediated by engagement with two structurally unrelated transmembrane receptors, p75(NTR) and TrkA, which are co-expressed in a variety of cells. The functional interactions of these receptors have been widely demonstrated and include complex formation, convergence of signaling pathways, and indirect interaction through adaptor proteins. Each domain of the receptors was shown to be important for the formation of TrkA and p75(NTR) complexes, but only the intramembrane and transmembrane domains seemed to be crucial for the creation of high-affinity binding sites. However, whether these occur through a physical association of the receptors is unclear. In the present work, we demonstrate by Förster resonance energy transfer that p75(NTR) and TrkA are physically associated through their intracellular (IC) domains and that this interaction occurs predominantly at the cell membrane and prior to NGF stimulation. Our data suggest that there is a pool of receptors dimerized before NGF stimulus, which could contribute to the high-affinity binding sites. We modeled the three-dimensional structure of the TrkA IC domain by homology modeling, and with this and the NMR-resolved structure of p75(NTR), we modeled the heterodimerization of TrkA and p75(NTR) by docking methods and molecular dynamics. These models, together with the results obtained by Förster resonance energy transfer, provide structural insights into the receptors' physical association.
authors: Centro de Microscopías Avanzadas, Universidad de Buenos Aires, C1428EHA Buenos Aires, Argentina.
authors: María Florencia
authors: MF
authors: Iacaruso
authors: Soledad
authors: S
authors: Galli
authors: Marcelo
authors: M
authors: Martí
authors: Jorge Ignacio
authors: JI
authors: Villalta
authors: Darío Ariel
authors: DA
authors: Estrin
authors: Elizabeth Andrea
authors: EA
authors: Jares-Erijman
authors: Lía Isabel
authors: LI
authors: Pietrasanta
mesh_terms: D000818:Animals; D019295:Computational Biology; D031541:Fluorescence Resonance Energy Transfer; D006624:Hippocampus / Q000737:chemistry; D051379:Mice; D020932:Nerve Growth Factor / Q000737:chemistry*; D016716:PC12 Cells; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000737:chemistry*; D020917:Receptor, trkA / Q000737:chemistry*; D040681:Structural Homology, Protein
chemical_list: D020800:Receptor, Nerve Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA