Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor protein expressed on the surface of microglia, the primary immune cells of the brain. TREM2 has recently emerged as a promising target for modulating the innate immune response in Alzheimer’s Disease (AD), with multiple therapeutic candidates currently in development. It functions by binding ligands to its extracellular domain and interacting with its co-signaling partner DAP12 in the membrane to propagate downstream signals; however, the molecular mechanisms underlying this process remain unclear. In addition, TREM2 can be expressed in a soluble form (sTREM2) through proteolytic cleavage or alternative splicing. Canonically cleaved sTREM2 is thought to play a neuroprotective role in the brain via direct inhibition of Aβ aggregation and by binding to Transgelin-2 (TG2), a neuronally expressed receptor that attenuates tau hyperphosphorylation. Alternatively spliced sTREM2 is less characterized and is not believed to share the same neuroprotective functions. To address these gaps in our understanding of (s)TREM2 structural dynamics, we apply multiscale molecular dynamics (MD) simulations across four projects: 1) We perform the first-ever simulations of the full TREM2-DAP12 complex embedded in a mimetic lipid membrane, using a combination of coarse-grained and atomistic modeling to assess how ligand binding propagates downstream signals. 2) We atomistically simulate the canonical proteolytically cleaved sTREM2 and the TREM2 Immunoglobulin-like ectodomain with brain-based phospholipids to identify fundamental ligand-binding patterns and how these are impacted by disease-associated mutations. 3) We conduct the first structural analysis of alternatively spliced sTREM2 isoforms and glycosylated (s)TREM2 to determine impacts of sequence-based differences and glycosylation on structure and function of (s)TREM2, giving insights into their unique roles in neurodegenerative disease. 4) We use computational tools to define the binding interface between sTREM2 and TG2 and subsequently leverage this knowledge to design TG2-targeting, sTREM2-derived peptides for treating tau pathology in AD. Across these projects, we successfully identified structural features critical for TREM2 signaling through the lipid membrane, enabling targeted drug design for microglia. We provide a fundamental understanding of how the heterogeneous sTREM2 pool functions as distinct molecular entities, investigate the roles of glycosylation and mutations, and directly characterize one of sTREM2’s neuroprotective mechanisms. Synergistically, these efforts leverage optimized computational resources to first uncover the core structural biology of (s)TREM2 and then apply these insights toward designing translatable therapeutic candidates.
