Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Thursday Speaker Abstracts

INSIGHTS INTO THE MECHANICS OF NEUROTROPHIN RECEPTOR SIGNALING FROM NMR SPECTROSCOPY Sergey A Goncharuk 2 ; Erik F Kot 5 ; Maria Luisa Franco 4 ; Daniel McKenzie 3 ; Dysha R Bedanokova 2 ; Vladislav A Lushpa 2 ; Anna G Savitskaya 2 ; Kalina Hristova 3 ; Marçal Vilar 4 ; Konstantin Mineev 1 ; 1 Goethe University Frankfurt, Frankfurt am Main, Germany 2 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation Neurotrophin receptors, namely three Trk receptor tyrosine kinases and p75NTR from the TNFR family, govern neuronal survival, differentiation, and plasticity, and contribute to the pathology of diverse cancers and neurodegenerative diseases. Despite their physiological and therapeutic importance, the molecular mechanism by which ligand binding propagates through the flexible juxtamembrane regions and short transmembrane helices to activate intracellular signaling remains poorly understood. Here, using NMR spectroscopy, fluorescence microscopy, and functional assays, we elucidate the structures and dynamics of Trk receptors in distinct functional states. We determined the spatial structures of dimeric transmembrane domains of TrkA and TrkB, assigning them by mutagenesis to active and pre-dimerized inactive conformations of the full-length receptors. Our results demonstrate that dimerization per se is largely uncoupled from receptor activation, indicating the presence of multiple dimeric states with distinct signaling properties. We further reveal the structural basis by which the antidepressant fluoxetine interacts with the TrkB transmembrane domain to modulate receptor activity, providing a molecular explanation for the drug’s long-term neuroplastic effects. Finally, we show that cross-linking at specific sites in the extracellular juxtamembrane (eJTM) region can switch TrkA from the inactive to active state, while mutations in this region impair ligand-induced activation. NMR analyses identify the eJTM as intrinsically disordered, suggesting that the region should interact with the growth factor and become rigid, in order to affect the state of the receptor transmembrane domains. The latter hypothesis found its confirmation in recent experiments on the TrkA/NGF complex. 3 Johns Hopkins University, Baltimore, MD, USA 4 Biomedicine Institute of Valencia, Valencia, Spain 5 Shenzhen MSU-BIT University, Faculty of Biology, Shenzhen, China

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