TREM2-apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants

Abstract

INTRODUCTION

Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (apoE) are among the strongest Alzheimer's disease (AD) genetic risk factors. TREM2 and apoE3 direct interaction has been established; however, molecular and structural insight into TREM2–apoE3 interactions and effects of AD-associated variants on TREM2–apoE3 interactions are not fully understood.

METHODS

We used consensus protein–protein docking and molecular dynamics simulations to determine an experimentally consistent TREM2–apoE3 complex structure and examine AD-associated TREM2 R47H, and apoE4 variants effects.

RESULTS

Our experimentally consistent TREM2–apoE3 complex structure identified new potential TREM2–apoE3 interactions alongside the known interactions. TREM2–apoE3 interactions impacted TREM2 and apoE3 structures and conformations. AD-associated TREM2 R47H and apoE4 variants altered TREM2–apoE binding mode and conformational stability.

DISCUSSION

This study determined an experimentally consistent TREM2–apoE3 complex structure and revealed a potential mechanism that AD-associated TREM2 R47H variant alters TREM2–apoE3 binding mode. Understanding TREM2–apoE interactions is important for developing therapeutics that regulate this interaction and prevent lost binding in AD-associated variants.

Highlights

• Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are two strong genetic risk factors for Alzheimer's disease (AD).
• An experimentally consistent TREM2–apoE3 complex structure was determined.
• New potential interaction interfaces between TREM2 and apoE3 were identified.
• TREM2–apoE3 interactions altered TREM2 and apoE3 conformation.
• AD-associated TREM2 R47H variant shifted apoE3 binding TREM2 into multimerization site. ApoE4 destabilized TREM2 and apoE conformations in TREM2–apoE complexes.