The Effects of Common Disease-Causing Variations on the Structure and Stability of TREM2: An In Silico Examination

Abstract

Single nucleotide variations in TREM2 are associated with both a late-onset form of Alzheimer's disease (AD) and a severe, early-onset demyelinating dementia, which can present in isolation as a variant of frontotemporal dementia (FTD) or with cystic bone lipomas in a condition called Nasu-Hakola disease (NHD). Published X-ray crystallography models of the TREM2 Ig domain have suggested that homozygous NHD- or FTD-causing mutations are grossly inactivating while variations associated with increased risk of AD in heterozygous patients are centered on a prominent surface patch of positively charged residues. This surface patch, which is not present in other members of the TREM family, has been proposed as the primary binding site for various polyanionic ligands. Importantly, AD-associated variations in TREM2 appear to alter the electrostatics or gross structure of this surface patch, but do not cause larger structural changes in published crystal structures. Because crystal structures for many rare variants involved in disease remain unpublished, the precise effects of these variants on binding site structure and dynamic motion remain unclear. Here we perform molecular dynamics using AMBER14 to study the effects of mutations associated with AD, NHD, and FTD on stability of TREM2. Preliminary results show increased conformational flexibility in FTD and NHD variants, which is unchanged in AD variants. Consistent with proposed losses of structural stability from previous reports, this increased flexibility is present near the putative ligand-binding region and could directly contribute to lost or weakened binding between TREM2 and putative ligands, such as the AD-associated proteins APOE and amyloid-β. Thus, further work toward thorough understanding of conformation and dynamical motion in this region of TREM2 remains critical to our understanding of the role of TREM2 in AD and other neurodegenerative diseases.