Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry
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Modulating hinge flexibility in the APP transmembrane domain alters γ-secretase

bioRxiv preprint first posted online Jul. 23, 2018

Authors/Editors: Alexander Götz
Nadine Mylonas
Philipp Högel
Mara Silber
Hannes Heinel
Simon Menig
Alexander Vogel
Hannes Feyrer
Daniel Huster
Burkhard Luy
Dieter Langosch
Christina Scharnagl
Claudia Muhle-Goll
Frits Kamp
Harald Steiner
Publication Date: 2018
Type of Publication: Journal Article

Intramembrane cleavage of the β-amyloid precursor protein C99 substrate by γ-secretase is implicated in Alzheimer´s disease pathogenesis. Since conformational flexibility of a di-glycine hinge in the C99 transmembrane domain (TMD) might be critical for γ-secretase cleavage, we mutated one of the glycine residues, G38, to a helixstabilizing leucine and to a helix-distorting proline. CD, NMR and hydrogen/deuterium exchange measurements as well as MD simulations showed that the mutations distinctly altered the intrinsic structural and dynamical properties of the TMD. However, although helix destabilization/unfolding was not observed at the initial ε-cleavage sites of C99, both mutants impaired γ-secretase cleavage and altered its cleavage specificity. Moreover, helix flexibility enabled by the di-glycine hinge translated to motions of other helix parts. Our data suggest that both local helix stabilization and destabilization in the di-glycine hinge may decrease the occurrence of enzyme-substrate complex conformations required for normal catalysis and that hinge mobility can be conducive for productive substrate-enzyme interactions.

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