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Steiner, A. ; Schlepckow, K.* ; Brunner, B.* ; Steiner, H.* ; Haass, C.* ; Hagn, F.

γ-Secretase cleavage of the Alzheimer risk factorTREM2 is determined by its intrinsic structural dynamics.

EMBO J. 39:e104247 (2020)
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Sequence variants of the microglial expressedTREM2 (triggering receptor expressed on myeloid cells 2) are a major risk factor for late onset Alzheimer's disease.TREM2 requires a stable interaction withDAP12 in the membrane to initiate signaling, which is terminated byTREM2 ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase. To understand the structural basis for the specificity of the intramembrane cleavage event, we determined the solution structure of theTREM2 transmembrane helix (TMH). Caused by the presence of a charged amino acid in the membrane region, theTREM2-TMHadopts a kinked structure with increased flexibility. Charge removal leads toTMHstabilization and reduced dynamics, similar to its structure in complex withDAP12. Strikingly, these dynamical features match with the site of the initial gamma-secretase cleavage event. These data suggest an unprecedented cleavage mechanism by gamma-secretase where flexibleTMHregions act as key determinants of substrate cleavage specificity.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Dynamics ; Intramembrane Protease ; Nmr ; Structure ; Trem2; Amyloid Precursor Protein; Magnetic-resonance Relaxation; Myeloid Cells-2 Trem2; Model-free Approach; Transmembrane Helix; Backbone Dynamics; Membrane-proteins; Domain; Site; Macromolecules
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Journal EMBO Journal, The
Quellenangaben Volume: 39, Issue: 20, Pages: , Article Number: e104247 Supplement: ,
Publisher Wiley
Publishing Place Heidelberg, Germany
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30505 - New Technologies for Biomedical Discoveries
30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-553600-001
G-503000-001
Grants Projekt DEAL
Gauss Centre for Supercomputing e.V.
German Research Foundation (DFG)
TUM Institute for Advanced Study - German Excellence Initiative
DOI 10.15252/embj.2019104247
WOS ID WOS:000562468200001
Scopus ID 85089695992
PubMed ID 32830336
WOS ID WOS:000582478100022
Erfassungsdatum 2020-10-20
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