RT Journal Article
SR Electronic
T1 Modulating hinge flexibility in the APP transmembrane domain alters γ-secretase cleavage
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 375006
DO 10.1101/375006
A1 Alexander Götz
A1 Nadine Mylonas
A1 Philipp Högel
A1 Mara Silber
A1 Hannes Heinel
A1 Simon Menig
A1 Alexander Vogel
A1 Hannes Feyrer
A1 Daniel Huster
A1 Burkhard Luy
A1 Dieter Langosch
A1 Christina Scharnagl
A1 Claudia Muhle-Goll
A1 Frits Kamp
A1 Harald Steiner
YR 2018
UL http://biorxiv.org/content/early/2018/11/20/375006.abstract
AB 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 helix-stabilizing 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.