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γ‐Secretase cleavage of the Alzheimer risk factor TREM 2 is determined by its intrinsic structural dynamics
Author(s) -
Steiner Andrea,
Schlepckow Kai,
Brunner Bettina,
Steiner Harald,
Haass Christian,
Hagn Franz
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019104247
Subject(s) - biology , cleavage (geology) , microbiology and biotechnology , biochemistry , biophysics , fracture (geology) , paleontology
Sequence variants of the microglial expressed TREM 2 (triggering receptor expressed on myeloid cells 2) are a major risk factor for late onset Alzheimer's disease. TREM 2 requires a stable interaction with DAP 12 in the membrane to initiate signaling, which is terminated by TREM 2 ectodomain shedding and subsequent intramembrane cleavage by γ‐secretase. To understand the structural basis for the specificity of the intramembrane cleavage event, we determined the solution structure of the TREM 2 transmembrane helix ( TMH ). Caused by the presence of a charged amino acid in the membrane region, the TREM 2‐ TMH adopts a kinked structure with increased flexibility. Charge removal leads to TMH stabilization and reduced dynamics, similar to its structure in complex with DAP 12. Strikingly, these dynamical features match with the site of the initial γ‐secretase cleavage event. These data suggest an unprecedented cleavage mechanism by γ‐secretase where flexible TMH regions act as key determinants of substrate cleavage specificity.