Protein recognition is chiefly mediated by the CDR2 region in TREM2 - an in silico characterization.

The Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is an immune receptor with three complementarity-determining regions (CDR1-3) that primarily interact with the receptor's ligands. Aside from its role in reducing inflammation, enhancing phagocytosis, and contributing to cellular maturation and survival, TREM2 also contributes to the pathophysiology of neurodegenerative disorders, cancer, and metabolic diseases. Therefore, understanding how the receptor interacts with its ligands is essential to mitigate its adverse effects and/or to foster the development of new therapeutic approaches. Thus, our research focused on understanding the interactions between TREM2 and its protein ligands: APOA1, APOA2, APOE3, APOE4, APOJ, C1q, Galectin-3, cyclophilin A, Heat shock protein 60 (HSP60), IL-34, IL-4, the SARS-CoV-2 membrane protein and the cholera toxin subunit B, TDP-43 using in silico methods, such as molecular docking and molecular dynamics simulations. TREM2 showed a higher affinity and stability with HSP60, APOA2, Cyclophilin A, Galectin-3, TDP-43 and C1q when compared to the other protein ligands. Notably, our data suggest that TREM2 interacts with its ligands predominantly through the CDR2 region by the following residues: N68, L69, W70, L71, L72, F74 and R76. Our findings indicate that the CDR2 region can be a crucial target for the development of inhibitory or agonistic approaches targeting the receptor's activity.