The Chemistry & Biochemistry Colloquium guest speaker on Nov. 20th will be Professor Haifan Wu: "Modeling ApoE/TREM2 complex using cross-linking mass spectrometry and protein-protein docking". Dr. Wu is an Assistant Professor in the Department of Chemistry at Wichitaw State University.

ABSTRACT

Alzheimer's disease (AD) is a devastating neurodegenerative disease with few disease-modifying therapies. Human genetics studies have identified two major genetic risk factors for late-onset AD—apolipoprotein E ( APOE ) and triggering receptor expressed on myeloid cells 2 ( TREM2 ). ApoE binds to the low-density lipoprotein receptor (LDLR) to facilitate the uptake of ApoE-lipoprotein particles, while TREM2 is a cell surface receptor expressed on microglia in the brain. The activation of TREM2 is essential for microglial survival, proliferation, and phagocytosis in order to carry out their protective functions against AD pathology. Recently, several studies have shown the activation of TREM2 signaling through the direct interaction between TREM2 and ApoE. In addition to the important role of ApoE/TREM2 interaction in AD pathogenesis, this interaction has been shown to induce immunosuppression of neutrophils within the tumor microenvironment. Therefore, a detailed understanding of this interaction could lead to novel therapeutic strategies targeting ApoE and TREM2. Although biophysical studies have been carried out to characterize this interaction, there is still no detailed structural model. Here we carried out chemical cross-linking of the ApoE/TREM2 complex followed by bottom-up mass spectrometry analysis to identify inter-protein cross-links, which were used as distance restraints to guide protein-protein docking using Haddock. We obtained the first structure model of the ApoE/TREM2 complex. We believe this model will facilitate future research of designing probe molecules to better understand the physiological functions of the ApoE/TREM2 interaction.