Mechanistic Disruption of the TREM2-DAP12 Transmembrane Complex by Alzheimer's Disease Mutations: A Multiscale...

Area of Science:

• Neuroscience
• Molecular Biology
• Biophysics

Background:

• Triggering Receptor Expressed on Myeloid cell 2 (TREM2) is crucial for microglial activation, interacting with DNAX-activation protein 12 (DAP12).
• TREM2 variants, particularly in the transmembrane domain (TMD), are linked to increased Alzheimer's disease (AD) risk, but mechanisms are unclear.
• Understanding TREM2-DAP12 complex dynamics is vital for elucidating AD pathogenesis.

Purpose of the Study:

• To investigate the structural and dynamic effects of TREM2 TMD mutations on TREM2-DAP12 complex formation.
• To analyze how specific mutations destabilize the TREM2-DAP12 interaction at an atomistic level.
• To develop a simulation and machine learning framework for studying transmembrane protein complexes in neurodegeneration.

Main Methods:

• Multiscale molecular dynamics (MD) simulations of TREM2-DAP12 complexes with various TMD mutations.
• Simulations conducted in a POPC:cholesterol lipid bilayer environment.
• Atomistic simulations combined with unsupervised machine learning to analyze conformational changes and interactions.

Main Results:

• Disease-associated TREM2 TMD mutations (e.g., W191X, K186A) destabilize the TREM2-DAP12 complex.
• Mutations induce isoform- and mutation-specific alterations in helix orientation, hydrogen bonding, and electrostatic interactions.
• The study identified specific residues and interactions critical for complex stability, extending previous findings on K186-D50 salt bridge.

Conclusions:

• TREM2 transmembrane domain mutations perturb the TREM2-DAP12 signaling interface, contributing to AD risk.
• The findings provide atomistic insights into how genetic variants impact membrane protein function in disease.
• A robust computational framework was established for studying disease-related transmembrane protein complexes.