Triggering receptor expressed on myeloid cells-2 (TREM2) is an immune receptor expressed on the surface of microglia, macrophages, dendritic cells, and osteoclasts. The TREM2-R47H variant is a significant risk factor for late-onset Alzheimer’s disease (AD), and the molecular basis of TREM2-R47H loss-of-function is an emerging area of TREM2 biology. Here, we report three high-resolution structures of the extracellular ligand-binding domains (ECD) of TREM2-R47H, apo wild-type (WT), and phosphatidylserine (PS)-bound WT TREM2 at 1.8 Å, 2.2 Å, and 2.2 Å resolutions, respectively. The structures revealed that Arg-47 plays a critical role in maintaining the structural fold of the complementarity-determining region 2 (CDR2) loop and the putative positive ligand–interacting surface (PLIS) in conformations capable of ligand interaction. This was exemplified in the PS-bound structure, in which the CDR2 loop and PLIS drove critical interactions with PS via surfaces that are disrupted in the variant. Together with in vitro and in vivo characterization, our structural findings elucidate the molecular mechanism underlying loss of ligand binding, putative oligomerization, and functional activity of TREM2-R47H. They also help unravel how decreased in vitro and in vivo stability of TREM2 contribute to loss of function in disease.

Molecular insights into effects of Alzheimer’s disease risk-variant R47H TREM2

2019 Fall National Meeting

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