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TREM2 and apoE3 direct interaction has been established; however, molecular and structural insight into TREM2\u2013apoE3 interactions and effects of AD\u2010associated variants on TREM2\u2013apoE3 interactions are not fully understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We used consensus protein\u2013protein docking and molecular dynamics simulations to determine an experimentally consistent TREM2\u2013apoE3 complex structure and examine AD\u2010associated TREM2 R47H, and apoE4 variants effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Our experimentally consistent TREM2\u2013apoE3 complex structure identified new potential TREM2\u2013apoE3 interactions alongside the known interactions. TREM2\u2013apoE3 interactions impacted TREM2 and apoE3 structures and conformations. AD\u2010associated TREM2 R47H and apoE4\u00a0 variants altered TREM2\u2013apoE binding mode and conformational stability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>This study determined an experimentally consistent TREM2\u2013apoE3 complex structure and revealed a potential mechanism that AD\u2010associated TREM2 R47H variant alters TREM2\u2013apoE3 binding mode. Understanding TREM2\u2013apoE interactions is important for developing therapeutics that regulate this interaction and prevent lost binding in AD\u2010associated variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Triggering receptor expressed on myeloid cells 2 (\n                            <jats:italic>TREM2<\/jats:italic>\n                            ) and apolipoprotein E (\n                            <jats:italic>APOE<\/jats:italic>\n                            ) are two strong genetic risk factors for Alzheimer's disease (AD).\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>An experimentally consistent TREM2\u2013apoE3 complex structure was determined.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>New potential interaction interfaces between TREM2 and apoE3 were identified.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>TREM2\u2013apoE3 interactions altered TREM2 and apoE3 conformation.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>AD\u2010associated TREM2\u00a0\u00a0R47H variant shifted apoE3 binding TREM2 into multimerization site. ApoE4 destabilized TREM2 and apoE conformations in TREM2\u2013apoE complexes.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70729","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T13:40:57Z","timestamp":1760449257000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["TREM2\u2010apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants"],"prefix":"10.1002","volume":"21","author":[{"given":"Rory A.","family":"Greer","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan 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