Abstract
Alzheimer's disease (AD) is now major cause of death worldwide and the most common cause of dementia in the elderly, marked by the appearance of amyloid-β (Aβ) plagues in the central nervous system. In recent years, “triggering receptor expressed in myeloid cells 2” (TREM2) protein variants have been identified as risk factors for AD and other neurodegenerative diseases. TREM2 is an immunomodulatory receptor composed of an extracellular V-type Ig domain followed by a short stalk, a single transmembrane helix, and a short cytoplasmic tail. TREM2 has been implicated in a wide array of functions related to microglial activation, survival, clustering, and phagocytosis. It signals as a complex with DNAX-activation protein 12 (DAP12). Moreover, TREM2 variant R47H impairs the microglia barrier function leading to decreased amyloid compaction and sever axonal dystrophy. The Ig domain of TREM2 is shed from the cell surface by an ADAM protease. The remaining transmembrane domain is then cleaved by γ-secretase releasing the soluble TREM2 (sTREM2) c-terminal fragment (CTF) and intracellular domain (ICD) which could potentially be biomarkers for AD. A mechanistic understanding of TREM2 regarding how it engaged its ligand(s), however, remains to be determined. In this study, we highlight structural features of TREM2 and its interaction with ligands using nuclear magnetic resonance (NMR) spectroscopy. This will provide insight of how different ligands might interact with the receptor and how these interactions alter TREM2 structure and trigger signaling. We also describe purification of the TREM2 transmembrane (TM) domain, its reconstitution into model membranes, and subsequent structural studies. Finally, we also describe efforts to characterize the TREM2-DAP12 complex by NMR methods. This work is supported by Bright Focus Foundation grant A2015565S.
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