Substrate dynamics governs recognition by \(\gamma\)-secretase

Novel recognition mechanism of \(\gamma\)-secretase revealed for the Alzheimer risk factor TREM2

[10.09.2020] A research team from the Technical University of Munich at the Department of Chemistry led by biochemist Franz Hagn together with colleagues at the LMU and the German Center for Neurodegenerative Diseases (DZNE) around Christian Haass provide unprecedented structural insights into the mechanism of substrate recognition of the Alzheimer disease risk factor TREM2 by the intra-membrane protease \(\gamma\)-secretase.

\(\gamma\)-secretase is an important protease that cleaves other proteins inside the cell membrane. This process is important for the induction of cellular signaling or for the targeted removal of proteins within the membrane. However, the features of a substrate protein required for the interaction with this protease have been subject of ongoing discussions.

Processing of an Alzheimer risk factor

The chosen substrate in this study was the protein triggering receptor expressed on myeloid cells 2 (TREM2) whose malfunction has been associated with early-onset Alzheimer’s disease. Thus, a detailed understanding on a molecular level is required to develop efficient therapies in the future.

Dynamics as a main factor for cleavage

The two research teams used an interdisciplinary approach consisting of an in-depth NMR characterization of the part of TREM2 that is located in the membrane together with the biological validation using \(\gamma\)-secretase cleavage assays. The NMR experiments conducted at the Bavarian NMR Center (BNMRZ) revealed that cleavage sites within TREM2 show high conformational dynamics and are therefore recognized by the protease.

Unprecedented mechanism revealed

The obtained insights represent an unprecedented mechanism where the protease \(\gamma\)-secretase scans for flexible parts of a substrate protein in the membrane and initiated a series of cleavage events at this position.
“These detailed insights on the mechanism of substrate recognition by \(\gamma\)-secretase opens up the way to alter the position of cleavage by mutagenesis or the treatment with a small molecule ligand, leading to the opportunity for therapeutic intervention”, says Franz Hagn.


Steiner A, Schlepckow K, Brunner B, Steiner H, Haass C and Hagn F, \(\gamma\)-secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics, EMBO J, e104247 (2020), in press (doi: 10.15252/embj.2019104247)

Further information

Funding for this study was provided by the Helmholtz Society, the Helmholtz Zentrum München, the TUM Institute for Advanced Study and the DFG-funded FOR2290.

Contact to this article

Prof. Dr. Franz Hagn
Professorship for Structural Membrane Biochemistry and Bavarian NMR Center
Department of Chemistry & Institute for Advanced Study
Technical University of Munich
Ernst-Otto-Fischer-Str. 2, 85748 Garching
Tel: +49 89 289 52624,