Dynamic structure of NGF and proNGF complexed with p75NTR: pro-peptide effect

Area of Science:

• Neuroscience
• Structural Biology
• Computational Biology

Background:

• Previous crystallographic studies defined 2:1 NGF/p75NTR and 2:2 proNGF/p75NTR complexes.
• Both mature and pro-neurotrophins exhibit variable stoichiometries in their interactions.

Purpose of the Study:

• To investigate the energetic and structural dynamics of NGF/p75NTR and proNGF/p75NTR interactions using Molecular Dynamics (MD) simulations.
• To elucidate how these interactions influence biological outcomes, particularly the dual role of NGF in neuronal survival and death.

Main Methods:

• Molecular Dynamics (MD) simulations were employed.
• Analysis of energetic and structural characteristics of NGF/p75NTR and proNGF/p75NTR complexes, including uncomplexed NGF.

Main Results:

• A 2:2 proNGF complex can transition to a 2:1 structure, facilitating sortilin interaction.
• Neurotrophin dimer structures are not fixed and undergo significant changes upon p75NTR binding.
• Different stoichiometries induce conformational changes in NGF, potentially explaining its dual role.

Conclusions:

• The study provides a new perspective on neurotrophin-receptor interactions and their functional consequences.
• Variable stoichiometries and induced structural modifications are key to understanding the dual roles of NGF in neuronal processes.
• This work offers insights into the molecular basis of neurotrophin signaling in neuronal cell death and survival.