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oai:figshare.com:article/33918792 2026-09-18T03:03:51Z category_1 category_4 category_12 category_14 category_15 category_19 category_873 category_46 category_734 category_64 category_135 portal_63 item_type_3 month_year_09_2026

XL-MS and De Novo Protein Design Identified a Common Motif for TREM2 Binding Doniesha Perera (25068426) Emmanuel Ajiboye (25068429) Kalana Pitakatuwana Hewavidanage (25068432) Sophia Wier (25068435) Vincent Duong (25068438) Haifan Wu (1566376) Biophysics Biochemistry Cell Biology Molecular Biology Neuroscience Pharmacology Chemical Sciences not elsewhere classified Immunology Biological Sciences not elsewhere classified Cancer Computational Biology triggering receptor expressed terminal region forms resolution molecular understanding onset alzheimer ’ linking mass spectrometry density lipoprotein receptor de novo </ transient binding pocket complex remains elusive based trem2 agonists ecd </ sub lipoprotein particles binding mode trem2 </ wraps around tumor microenvironment several studies robust framework results establish protective functions neutrophils within interprotein cross induce immunosuppression important role identify intra hydrophobic tip direct interaction developing miniprotein data support common motif clinical importance chemical cross ad pathology ad pathogenesis Apolipoprotein E (<i>APOE</i>) and triggering receptor expressed on myeloid cells 2 (<i>TREM2</i>) are the two strongest genetic risk factors of late-onset Alzheimer’s disease. ApoE binds to the low-density lipoprotein receptor (LDLR) to facilitate the uptake of ApoE-lipoprotein particles. TREM2 is a cell surface receptor expressed on microglia in the brain. The activation of TREM2 is essential for microglia to carry out protective functions against AD pathology. Several studies have shown that TREM2 signaling is activated through direct interaction between TREM2 and ApoE. In addition to its important role in AD pathogenesis, the ApoE/TREM2 interaction has been shown to induce immunosuppression of neutrophils within the tumor microenvironment. Despite its clinical importance, a high-resolution molecular understanding of the complex remains elusive. Here, we carried out chemical cross-linking mass spectrometry (XL-MS) analysis of the ApoE3/TREM2_ECD complex to identify intra- and interprotein cross-links, which were used as restraints to guide integrative protein–protein docking. Our data support a binding model in which a helix–loop–helix motif within the ApoE3 hinge and C-terminal region forms a transient binding pocket that wraps around the hydrophobic tip of the TREM2 ectodomain. This model is further supported by <i>de novo</i>-designed miniprotein binders, which show the same binding mode as identified by our XL-MS experiment. These results establish a robust framework for developing miniprotein-based TREM2 agonists. 2026-09-17T00:00:00Z Dataset Dataset 10.1021/acschemneuro.6c00310.s003 https://figshare.com/articles/dataset/XL-MS_and_De_Novo_Protein_Design_Identified_a_Common_Motif_for_TREM2_Binding/33918792 CC BY-NC 4.0