Multimerization of TREM2 is impaired by Alzheimer's disease-associated variants.

ABSTRACT:

Introduction

The immune receptor triggering receptor expressed on myeloid cells 2 (TREM2) is among the strongest genetic risk factors for Alzheimer's disease (AD) and is a therapeutic target. TREM2 multimers have been identified in crystallography and implicated in the efficacy of antibody therapeutics; however, the molecular basis for TREM2 multimerization remains poorly understood.

Methods

We used molecular dynamics simulations and binding energy analysis to determine the effects of AD-associated variants on TREM2 multimerization and validated with experimental results.

Results

TREM2 trimers remained stably bound, driven primarily by salt bridge between residues D87 and R76 at the interface of TREM2 units. This salt bridge was disrupted by the AD-associated variants

SUBMITTER: Dean HB 

PROVIDER: S-EPMC11497687 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature