Molecular basis for the loss-of-function effects of the Alzheimer's disease-associated R47H variant of the immune receptor TREM2

Athena Sudom, Santosh Talreja, Jean Danao, Eric Bragg, Rob Kegel, Xiaoshan Min, Jason Richardson, Zhongqi Zhang, Nikolai Sharkov, Edoardo Marcora, Steve Thibault, Jodi Bradley, Steve Wood, Ai Ching Lim, Hang Chen, Songli Wang, Ian N. Foltz, Shilpa Sambashivan, Zhulun Wang

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor expressed on the surface of microglia, macrophages, dendritic cells, and osteoclasts. The R47H TREM2 variant is a significant risk factor for late-onset Alzheimer's disease (AD), and the molecular basis of R47H TREM2 loss of function is an emerging area of TREM2 biology. Here, we report three high-resolution structures of the extracellular ligand-binding domains (ECDs) of R47H TREM2, apo-WT, and phosphatidylserine (PS)-bound WT TREM2 at 1.8, 2.2, and 2.2 Å, respectively. The structures reveal that Arg47 plays a critical role in maintaining the structural features of the complementarity-determining region 2 (CDR2) loop and the putative positive ligand-interacting surface (PLIS), stabilizing conformations capable of ligand interaction. This is exemplified in the PSbound structure, in which the CDR2 loop and PLIS drive 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 R47H TREM2. They also help unravel how decreased in vitro and in vivo stability of TREM2 contribute to loss of function in disease.

Original languageEnglish
Pages (from-to)12634-12646
Number of pages13
JournalJournal of Biological Chemistry
Volume293
Issue number32
DOIs
StatePublished - 10 Aug 2018

Fingerprint

Dive into the research topics of 'Molecular basis for the loss-of-function effects of the Alzheimer's disease-associated R47H variant of the immune receptor TREM2'. Together they form a unique fingerprint.

Cite this