The Impact of the ‘Austrian’ Mutation of the Amyloid Precursor Protein Transmembrane Helix is Communicated to the Hinge Region

摘要

The transmembrane helix of the amyloid precursor protein is subject to proteolytic cleavages by γ-secretase at different sites resulting in Aβ peptides of different length and toxicity. A num- ber of point mutations within this transmembrane helix alter the cleavage pattern thus enhancing production of toxic Aβ peptide species that are at the root of familial Alzheimer’s dis- ease. Here, we investigated how one of the most devastating mutations, the ‘Austrian’ mutation T43I, affects this trans- membrane helix. Site-resolved deuterium/hydrogen amide ex- change experiments reveal that the mutation destabilizes amide hydrogen bonds in the hinge which connects dimeriza- tion and cleavage regions. Weaker intrahelical hydrogen bonds at the hinge may enhance helix bending and thereby affect recognition of the transmembrane substrate by the enzyme and/or presentation of its cleavage sites to the catalytic cleft.