DOI: 10.5061/dryad.0000000gn
title: The flexible stalk domain of sTREM2 modulates its interactions with brain-based phospholipids

description: The microglial surface protein Triggering Receptor Expressed on Myeloid
 Cells 2 (TREM2) plays a critical role in mediating brain homeostasis and
 inflammatory responses in Alzheimer’s disease (AD). The soluble form of
 TREM2 (sTREM2) exhibits neuroprotective effects in AD, though the
 underlying mechanisms remain elusive. Moreover, differences in ligand
 binding between TREM2 and sTREM2, which have major implications for their
 roles in AD pathology, remain unexplained. To address these knowledge
 gaps, we conducted the most computationally intensive molecular dynamics
 simulations to date of human (s)TREM2, exploring their interactions with
 key damage- and lipoprotein-associated phospholipids and the impact of the
 AD-risk mutation R47H. Our results demonstrate that the flexible stalk
 domain of sTREM2 serves as the molecular basis for differential ligand
 binding between sTREM2 and TREM2, facilitated by its role in modulating
 the dynamics of the Ig-like domain and altering the accessibility of
 canonical ligand binding sites. We identified a novel ligand binding site
 on sTREM2, termed the ‘Expanded Surface 2’, which emerges due to
 competitive binding of the stalk with the Ig-like domain. Additionally, we
 observed that the stalk domain itself functions as a site for ligand
 binding, with increased binding frequency in the presence of R47H. This
 suggests that sTREM2’s neuroprotective role in AD may, at least in part,
 arise from the stalk domain’s ability to rescue dysfunctional ligand
 binding caused by AD-risk mutations. Lastly, our findings indicate that
 R47H-induced dysfunction in TREM2 may result from both diminished ligand
 binding due to restricted complementarity-determining region 2 loop
 motions and an impaired ability to differentiate between ligands,
 proposing a novel mechanism for loss-of-function. In summary, these
 results provide valuable insights into the role of sTREM2 in AD pathology,
 laying the groundwork for the design of new therapeutic approaches
 targeting (s)TREM2 in AD.
description: # The flexible stalk domain of sTREM2 modulates its interactions with
 brain-based phospholipids Dataset DOI:
 [10.5061/dryad.0000000gn](10.5061/dryad.0000000gn) ## Description of the
 data and file structure MD trajectories, structure files, and analysis
 files (RMSD, RMSF) as outlined in the associated eLife
 paper. [https://doi.org/10.7554/eLife.102269.2](https://doi.org/10.7554/eLife.102269.2) ### Files and variables #### File: eLife_Data_Availability.zip **Description:** This directory contains molecular dynamics (MD) trajectories, structure files, and analysis outputs (RMSD and RMSF) corresponding to the simulations described in the associated eLife paper. **Folder Structure** The top-level directory contains two main folders: * `WT/` — Wild-type (s)TREM2 simulations * `R47H/` — R47H mutant (s)TREM2 simulations Within each of these, subdirectories are organized by the simulated system. For example: * `PSIG/` — Simulations of the Ig-like domain of TREM2 in the presence of phosphatidylserine * Additional folders represent other systems described in the paper. Each system folder (e.g., `PSIG/`) contains replicate simulation folders named numerically (e.g., `1/`, `2/`, etc.). **File Types** Each numbered replicate folder includes the following files: * `.gro` — GROMACS structure file of the simulated system (used to define atomic coordinates) * `.xtc` — GROMACS trajectory file (requires corresponding `.gro` file for visualization or analysis) * `.xvg` — GROMACS output of calculated RMSD or RMSF values Additional FilesSome directories also include: * `.tcl` — TCL scripts used for VMD-based analysis (run through the VMD Tk Console) * `.txt` — Output files generated from TCL script analysis **Usage** To visualize or analyze a trajectory, load the `.xtc` and corresponding `.gro` file in GROMACS, VMD, or your preferred MD analysis tool. Analysis files (.xvg) can be plotted using tools such as Grace or matplotlib. ## Code/software Trajectories can be viewed in VMD or other similar molecular visualization tool. Analysis of data can be performed with python, gromacs, or other similar features.  ## Access information Other publicly accessible locations of the data: * N/A Data was derived from the following sources: * GROMACS MD simulation.