Simulation of neurotrophin receptor transmembrane helix interactions reveals active states and distinct signaling mechanisms

Abstract

Neurotrophin (NT) receptor signaling regulates neuronal survival, axonal and dendritic network maintenance, differentiation, and synaptic plasticity. Signaling is initiated by NT binding to the extracellular domain of NT receptor dimers, leading to activation of the receptor and signal propagation intracellularly. How this activating signal is mediated by the single-pass transmembrane (TM) helical domain of the receptor, and what the relation between domain sequence and signaling mechanism is, remains unclear. The structure and dynamics of the TM domain of the receptor dimers in the active and inactive states for intracellular signaling are still elusive, with NMR structures capturing only a single state. Here, we carried out unbiased and enhanced sampling molecular dynamics simulations of the TM domain dimers of the wild-type p75, TrkA and TrkB NT receptors and selected mutants in micelle and bilayer lipid environments at atomistic and coarse-grained levels of representation. The coarse-grained simulations enabled exploration of multiple states of the TM domain dimers and revealed the influence of the lipid environment on the TM helix arrangements. From the simulations, we identify active and inactive TM helix arrangements of the p75 and TrkA receptors that are supported by experimental data and suggest two different signaling mechanisms through the C-terminal regions of the TM helices. For TrkB, a single dominant but less energetically stable arrangement of the TM domain dimer is observed. These findings have implications for mechanistic studies of NT receptor signaling and the design of neuroprotective drugs to stabilize specific states of the TM domain of the receptors. Significance StatementNeurotrophins regulate neuronal survival, growth and differentiation during development, and play a role in many neurodegenerative and psychiatric disorders. They initiate signaling through the cell membrane by associating extracellularly with transmembrane receptors. The transmembrane helical domain of the neurotrophin receptors is responsible for transmitting the activation signal to the cell interior. However, how the transmembrane domain mediates signal transmission and the relation between its sequence and signaling mechanism remain unclear. Here, by employing state-of-the-art molecular dynamics simulation techniques, we identify active and inactive states of the transmembrane domains of the three main neurotrophin receptors that support distinct transmembrane signaling mechanisms for these receptors. Our results have implications for mechanistic studies of neurotrophin signaling and the design of neuroprotective drugs.