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Adv."],"published-print":{"date-parts":[[2026,6,12]]},"abstract":"<jats:p>AMPA-type glutamate receptors (AMPARs) are complex assemblies whose compositional heterogeneity underlies diverse excitatory signaling in the mammalian brain. Here, we determine high-resolution cryo\u2013electron microscopy (cryo-EM) structures of native AMPAR complexes rapidly purified from mouse brain. These structures capture receptors in physiologically relevant assemblies containing distinct combinations of transmembrane AMPA receptor regulatory protein (TARP) and cornichon homolog (CNIH) auxiliary subunits and reveal unambiguous density for the brain-specific protein SynDIG4. The resolved topology and interaction network of SynDIG4 show that it engages the receptor through a CNIH-dependent interface and occupies a position adjacent to structural elements of GluA1 implicated in trafficking and synaptic plasticity. The diversity of auxiliary stoichiometries observed across native complexes highlights a flexible organizational scheme through which AMPARs incorporate distinct regulatory partners. These findings illuminate the organization of native AMPAR assemblies and define the structural context for SynDIG4 function in the mammalian brain.<\/jats:p>","DOI":"10.1126\/sciadv.aee7973","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:58:47Z","timestamp":1781287127000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Native AMPA receptor architecture reveals SynDIG4 engagement and auxiliary subunit heterogeneity"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8483-7902","authenticated-orcid":true,"given":"Chengli","family":"Fang","sequence":"first","affiliation":[{"name":"Vollum Institute, Oregon Health &amp; Science University, Portland, OR 97239, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8549-2360","authenticated-orcid":true,"given":"Eric","family":"Gouaux","sequence":"additional","affiliation":[{"name":"Vollum Institute, Oregon Health &amp; 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