Functional insights from biophysical study of TREM2 interactions with ApoE and Aβ1-42
| Autor: | Berevan Baban, Melissa D. Stuchell-Brereton, Colin E. Kluender, Jennifer Alexander-Brett, Daniel L. Kober, Michael R. Strickland, Yuhua Song, Carl Frieden, Deborah F. Steinberg, Hunter B. Dean, David M. Holtzman, Samantha S. Nelson, Erik D. Roberson, Tom J. Brett |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Apolipoprotein E Epidemiology Amyloid beta Lipid-anchored protein Immune receptor Cellular and Molecular Neuroscience 03 medical and health sciences 0302 clinical medicine Developmental Neuroscience medicine Receptor Neuroinflammation 030304 developmental biology 0303 health sciences Innate immune system Microglia biology Chemistry TREM2 Health Policy Neurodegeneration medicine.disease Cell biology Psychiatry and Mental health 030104 developmental biology medicine.anatomical_structure biology.protein Neurology (clinical) Geriatrics and Gerontology 030217 neurology & neurosurgery Function (biology) |
| DOI: | 10.1101/2020.02.24.963264 |
| Popis: | INTRODUCTIONTREM2 is an innate immune receptor expressed on myeloid cells including microglia in the brain. How TREM2 engages different ligands remains poorly understood.METHODSWe used comprehensive BLI analysis to investigate the TREM2 interactions with ApoE and monomeric amyloid beta (mAβ42).RESULTSTREM2 binding did not depend on ApoE lipidation, and there were only slight differences in affinity observed between ApoE isoforms (E4 > E3 > E2). Surprisingly, disease-linked TREM2 variants within a “basic patch” minimally impact ApoE binding. Instead, TREM2 has a unique hydrophobic surface that can bind to ApoE. This direct engagement requires the hinge region of ApoE. TREM2 directly binds mAβ42 and can potently inhibit Aβ42 polymerization, suggesting a potential mechanism for soluble TREM2 (sTREM2) in preventing AD pathogenesis.DISCUSSIONThese findings demonstrate that TREM2 has at least two separate surfaces to engage ligands and uncovers a potential function for sTREM2 in directly inhibiting Aβ polymerization. |
| Databáze: | OpenAIRE |
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