# Simulation of Neurotrophin Receptor Transmembrane Helix Interactions Reveals Active States and Distinct Signaling Mechanisms

## TL;DR

This study uses simulations to explore how neurotrophin receptors transmit signals through their transmembrane domains, revealing active states and different signaling mechanisms.

## Contribution

The study identifies distinct active and inactive states of transmembrane helix arrangements in neurotrophin receptors and proposes different signaling mechanisms.

## Key findings

- Active and inactive TM helix arrangements of p75 and TrkA receptors were identified and supported by experimental data.
- Two different signaling mechanisms are suggested through the C-terminal regions of TM helices in p75 and TrkA.
- TrkB shows a single dominant TM domain dimer arrangement that is less energetically stable.

## Abstract

Neurotrophin (NT) receptor signaling regulates neuronal
survival,
axonal and dendritic network maintenance, differentiation, and synaptic
plasticity. Signaling is initiated by binding of NT 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 remain 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.