γ‐Secretase cleavage of the Alzheimer risk factor TREM 2 is determined by its intrinsic structural dynamics

Autor: Franz Hagn, Kai Schlepckow, Bettina Brunner, Harald Steiner, Andrea Steiner, Christian Haass
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Protein Conformation
alpha-Helical

chemistry [Membrane Glycoproteins]
Magnetic Resonance Spectroscopy
genetics [Amyloid Precursor Protein Secretases]
genetics [Alzheimer Disease]
metabolism [Microglia]
0302 clinical medicine
genetics [Membrane Glycoproteins]
Membrane region
Structural Biology
Risk Factors
genetics [Adaptor Proteins
Signal Transducing]

TREM2
genetics [Receptors
Immunologic]

Receptors
Immunologic

Receptor
chemistry.chemical_classification
0303 health sciences
Membrane Glycoproteins
General Neuroscience
Circular Dichroism
metabolism [Receptors
Immunologic]

Articles
dynamics
Amino acid
ddc
Molecular Docking Simulation
Transmembrane domain
genetics [Membrane Proteins]
Ectodomain
chemistry [Receptors
Immunologic]

Microglia
metabolism [Alzheimer Disease]
Signal Transduction
Intramembrane protease
Biology
Molecular Dynamics Simulation
Cleavage (embryo)
genetics [Signal Transduction]
General Biochemistry
Genetics and Molecular Biology

Article
metabolism [Cell Membrane]
03 medical and health sciences
metabolism [Adaptor Proteins
Signal Transducing]

Protein Domains
Alzheimer Disease
ddc:570
Humans
chemistry [Membrane Proteins]
structure
Molecular Biology
030304 developmental biology
Adaptor Proteins
Signal Transducing

General Immunology and Microbiology
Cell Membrane
enzymology [Alzheimer Disease]
Membrane Proteins
Post-translational Modifications
Proteolysis & Proteomics

chemistry [Adaptor Proteins
Signal Transducing]

NMR
metabolism [Amyloid Precursor Protein Secretases]
HEK293 Cells
chemistry
Mutation
biology.protein
Biophysics
Amyloid Precursor Protein Secretases
metabolism [Membrane Glycoproteins]
030217 neurology & neurosurgery
metabolism [Membrane Proteins]
intramembrane protease
Neuroscience
Zdroj: The EMBO journal 39(20), e104247 (2020). doi:10.15252/embj.2019104247
The EMBO Journal
DOI: 10.15252/embj.2019104247
Popis: 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.
NMR analyses of the TREM2 transmembrane helix in its native lipid environments reveal the structural basis for site‐specific intramembrane proteolysis of this disease‐associated microglial signaling receptor.
Databáze: OpenAIRE
načítá se...