Fig. 3

Structural insights into TREM2 ligand recognition and the impact of LOF mutation. a Structural alignment of TREM2 CV (PDB: 5UD7) vs. TREM2 R47H (PDB: 5UD8). The top cartoon depiction shows the overall structure of TREM2 R47H (in beige) superposed with TREM2 CV (in grey). The β-strands and CDR loops of Ig-like domain of TREM2 were labeled from A to G and from CDR1 to CDR3, respectively. The red dashed arrows indicate the conformational change of CDR2 loop caused by R47H mutation. At the bottom, the left panel of the zoom-in image shows that R47 is involved in an interacting network with S65, N68 and R77 to stabilize regular TREM2 Ig folding of the C’’ strain and CDR2 loop in TREM2 CV. The right panel of the zoom-in image illustrates that H47 (in pink) forms a new aromatic π–π stacking with H67 (red dashed line), leading to a turning of H67 (red dashed arrow) from normal orientation (grey H67) and CDR2 conformation change (black dashed arrow). b The embedded phosphatidylserine (PS) binding pocket is created by two adjacent TREM2 molecules (TREM2 and TREM2’). The original structures of TREM2 are shown with electrostatic surface area and PS molecule is presented with sticks for better visualization (modified from PDB: 6B8O). Green indicates the surface of TREM2, and Cyan indicates the surface of TREM2’. Blue highlights indicate the NH groups and red highlights the CO groups of the protein. In the zoom-in image, blue sticks/surface show the hydrophilic residues interacting with PS head groups, and yellow sticks/surface illustrate the hydrophobic neck of the ligand binding pocket. c The structural model of PS binding to TREM2 dimer (modified from PDB: 6B8O). Highlighted sticks in the zoom-out panel show all the putative interactions and the physical distances between interacting atoms (dashed bar) in the PS binding sites. Dark green sticks show the residues from TREM2 interacting with the PS molecule; light cyan sticks show the residues from TREM2’ interacting with the PS molecule. Residues with apostrophe marks are from the second TREM2 molecule (TREM2’)