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

David Saeb
Emma E Lietzke
Daisy I Fuchs
Emma C Aldrich
Kimberley D Bruce
Kayla G Sprenger author has email address

Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, United States
Department of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, United States

https://doi.org/10.7554/eLife.102269.2

Open access
Copyright information

Figures and data

Overview of structural domains in sTREM2 and full-length TREM2
(A) Pre-MD structure of sTREM2^WT. (B) Full sequence of TREM2, indicating significant structural domains.

The stalk of sTREM2^WT modulates the Ig-like domain via binding to Surface 1
(A) Distance between CDR loop residues 45 and 70 over time for WT and R47H models of sTREM2 and TREM2 (Ig), averaged across six replicates. Error bars represent the SEM. (B) Temporally averaged Cα RMSF of the isolated Ig-like domain of WT and R47H sTREM2 compared to the Ig-like domain of TREM2, averaged across six replicates. Error bars represent the SEM. (C-D) Cα RMSD of (C) WT and (D) R47H models of sTREM2 and TREM2 over time during the initial simulations, with corresponding snapshots shown for the starting and equilibrated structures in each case. The stalk domain of sTREM2 is shown in dark purple, and the CDR2 loop of TREM2 is shown in light purple. (E-F) Normalized fractional occupancy of residues in the Ig-like domain of (E) sTREM2^WT and (F) sTREM2^R47H by the stalk during the initial simulations.

The stalk of sTREM2^WT modulates phospholipid binding
(A-D) Normalized fractional occupancy of residues in (A) Ig^WT by SOPS, (B) sTREM2^WT by SOPS, (C) Ig^WT by SOPC, and (D) sTREM2^WT by SOPC, averaged across seven, five, five, and six 150-ns simulations, respectively. (E-H) VMD snapshots of representative structures from the PL/(s)TREM2^WT simulations, with PLs and corresponding complex binding free energies shown in matching colors.

The R47H mutation decreases ligand discrimination but increases binding to the flexible stalk domain
(A-D) Normalized fractional occupancy of residues in (A) Ig^R47H by SOPS, (B) sTREM2^R47H by SOPS, (C) Ig^R47H by SOPC, and (D) sTREM2^R47H by SOPC, averaged across four, seven, six, and eight 150-ns simulations, respectively. (E-H) VMD snapshots of representative structures from the PL/(s)TREM2^R47H simulations, with PLs and corresponding complex binding free energies shown in matching colors. (I) Comparison of the binding free energies averaged across all WT and R47H models for each PL/protein system. Errors bars represent the standard error of the mean.

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