Related Experiment Video
Updated: Dec 11, 2025
Imaging the Intracellular Trafficking of APP with Photoactivatable GFP
Published on: October 17, 2015
γ-Secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics
Andrea Steiner1,2, Kai Schlepckow3, Bettina Brunner3
1Bavarian NMR Center at the Department of Chemistry and Institute for Advanced Study, Technical University of Munich, Garching, Germany.
Abstract:
Sequence variants of the microglial expressed TREM2 (triggering receptor expressed on myeloid cells 2) are a major risk factor for late onset Alzheimer's disease. 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 γ-secretase. 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-TMH 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 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.
Insights
Sequence variants in triggering receptor expressed on myeloid cells 2 (TREM2) are linked to Alzheimer's disease. Its transmembrane helix flexibility dictates gamma-secretase cleavage, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Structural Biology
Background:
- Sequence variants of microglial TREM2 (triggering receptor expressed on myeloid cells 2) are a significant risk factor for late-onset Alzheimer's disease.
- TREM2 signaling initiates via interaction with DAP12, and is terminated by ectodomain shedding and intramembrane cleavage by γ-secretase.
Purpose of the Study:
- To elucidate the structural basis for the specificity of TREM2 intramembrane cleavage by γ-secretase.
- To understand how TREM2 transmembrane helix (TMH) structure and dynamics influence cleavage specificity.
Main Methods:
- Solution structure determination of the TREM2 transmembrane helix (TMH).
- Analysis of TMH structure and dynamics in relation to charged amino acid presence and DAP12 interaction.
Main Results:
- The TREM2-TMH adopts a kinked, flexible structure due to a charged amino acid in the membrane region.
- Charge removal stabilizes the TMH, reducing dynamics and mimicking its structure when bound to DAP12.
- These dynamical features correlate with the site of initial γ-secretase cleavage.
Conclusions:
- TREM2 TMH flexibility is a key determinant of γ-secretase cleavage specificity.
- This suggests an unconventional cleavage mechanism by γ-secretase, driven by substrate TMH dynamics.
- Findings provide insights into Alzheimer's disease pathogenesis and potential therapeutic strategies targeting TREM2 processing.
More Related Videos
09:31Visualization of Amyloid β Deposits in the Human Brain with Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry
Published on: March 7, 2019
06:40Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
Published on: January 25, 2018
Related Concept Videos
03:03Amyloid Fibrils
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
03:03Amyloid Fibrils
01:00Enzyme-linked Receptors
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...