Interaction between the transmembrane domains of neurotrophin receptors p75 and TrkA mediates their reciprocal activation

12 páginas, 6 figuras. CSs fromTrkA-TMD and p75-TMD are deposited in the Biological Magnetic Resonance Data Bank with accession number 25872for TrkA-TMD and 19673 for p75-TMD.
The neurotrophin receptors p75 and tyrosine protein kinase receptor A (TrkA) play important roles in the development and survival of the nervous system. Biochemical data suggest that p75 and TrkA reciprocally regulate the activities of each other. For instance, p75 is able to regulate the response of TrkA to lower concentrations of nerve growth factor (NGF), and TrkA promotes shedding of the extracellular domain of p75 by α-secretases in a ligand-dependent manner. The current model suggests that p75 and TrkA are regulated by means of a direct physical interaction; however, the nature of such interaction has been elusive thus far. Here, using NMR in micelles, multiscale molecular dynamics, FRET, and functional studies, we identified and characterized the direct interaction between TrkA and p75 through their respective transmembrane domains (TMDs). Molecular dynamics of p75-TMD mutants suggests that although the interaction between TrkA and p75 TMDs is maintained upon mutation, a specific protein interface is required to facilitate TrkA active homodimerization in the presence of NGF. The same mutations in the TMD protein interface of p75 reduced the activation of TrkA by NGF as well as reducing cell differentiation. In summary, we provide a structural model of the p75-TrkA receptor complex necessary for neuronal development stabilized by TMD interactions.
This study was supported bythe Spanish Ministry of Economy and Competitiveness (project BFU2013-42746-P and SAF2017-84096-R), the GeneralitatValenciana Prometeo grant 2018/055 (to M. V.), and the National Institutes of Health GM068619 (to K. H.). NMR studies of TRKA-TM and p75-TM were supported by the Russian Science Founda-tion (grant no. 19-74-30014 to A. S. A.)