The flexible stalk domain of sTREM2 modulates its interactions with brain-based phospholipids

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.