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TREM2 requires a stable interaction with DAP12 in the membrane to initiate signaling, which is terminated by TREM2 ectodomain shedding and subsequent intramembrane cleavage by \u03b3\u2010secretase. To understand the structural basis for the specificity of the intramembrane cleavage event, we determined the solution structure of the TREM2 transmembrane helix (TMH). Caused by the presence of a charged amino acid in the membrane region, the TREM2\u2010TMH adopts a kinked structure with increased flexibility. Charge removal leads to TMH stabilization and reduced dynamics, similar to its structure in complex with DAP12. Strikingly, these dynamical features match with the site of the initial \u03b3\u2010secretase cleavage event. These data suggest an unprecedented cleavage mechanism by \u03b3\u2010secretase where flexible TMH regions act as key determinants of substrate cleavage specificity.<\/jats:p>","DOI":"10.15252\/embj.2019104247","type":"journal-article","created":{"date-parts":[[2020,8,24]],"date-time":"2020-08-24T07:39:06Z","timestamp":1598254746000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["\u03b3\u2010Secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics"],"prefix":"10.1038","volume":"39","author":[{"given":"Andrea","family":"Steiner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Schlepckow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Brunner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Steiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4869-1627","authenticated-orcid":false,"given":"Christian","family":"Haass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1315-459X","authenticated-orcid":false,"given":"Franz","family":"Hagn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,24]]},"reference":[{"key":"BFEMBJ2019104247_CR1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s10858-007-9214-2","volume":"40","author":"EJ d'Auvergne","year":"2008","unstructured":"d'Auvergne EJ, Gooley PR (2008a) Optimisation of NMR dynamic models I. 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