Biophysical mapping of TREM2-ligand interactions reveals shared surfaces for engagement of multiple AD ligands
Biophysical mapping of TREM2-ligand interactions reveals shared surfaces for engagement of multiple AD ligands
Abstract TREM2 is a signaling receptor expressed on microglia that has emerged as an important potential drug target for Alzheimer’s disease and other neurodegenerative diseases. While a number of TREM2 signaling ligands have been identified, little is known regarding the structural details of how it engages them. To better understand this, we created a protein library of 28 different TREM2 variants and 11 different sTREM2 variants that could be used to map interactions with various ligands using biolayer interferometry (BLI). The variants are located in previously identified putative binding surfaces on TREM2 called the hydrophobic site, basic site, and site 2. We found that mutations to the hydrophobic site ablated binding to apoE4, oAb42, and TDP-43. Competition binding experiments further supported that apoE4 and oAb42 share overlapping binding sites on TREM2. In contrast, binding to IL-34 was mediated by the basic site at a surface centering on R76. Competition binding experiments validated a unique site for IL-34, showing little to no competition with either oAb42 or apoE4. Altogether, our results suggest that TREM2 utilizes the hydrophobic site (consisting of CDR1, CDR2, and CDR3) as a common site to engage multiple ligands, and further implies that pharmaceutical strategies targeting this surface might be effective to modulate TREM2 functions.
Greven Jessica A.、Alexander-Brett Jennifer M.、Brett Tom J.、Greer Rory A.、Wydra Joshua R.、Camitta Christopher、Song Yuhua
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine||Center for Regenerative Medicine, Washington University School of Medicine||Department of Pathology and Immunology, Washington University School of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine||Center for Regenerative Medicine, Washington University School of Medicine||Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine||Hope Center for Neurological Disorders, Washington University School of Medicine||Department of Cell Biology and Physiology, Washington University School of MedicineDepartment of Biomedical Engineering, University of Alabama at BirminghamDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of MedicineDepartment of Biomedical Engineering, University of Alabama at Birmingham
神经病学、精神病学生物科学研究方法、生物科学研究技术生物物理学
Greven Jessica A.,Alexander-Brett Jennifer M.,Brett Tom J.,Greer Rory A.,Wydra Joshua R.,Camitta Christopher,Song Yuhua.Biophysical mapping of TREM2-ligand interactions reveals shared surfaces for engagement of multiple AD ligands[EB/OL].(2025-03-28)[2025-06-17].https://www.biorxiv.org/content/10.1101/2024.05.23.595592.点此复制
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