Capture of Amyloid Precursor Protein Fragments by an Engineered Water-Soluble γ-Secretase

We have investigated amyloid plaque generation by overcoming the structural and hydrophobic constraints of the γ-secretase complex. We engineered the first fully water-soluble variant of the γ-secretase transmembrane scaffold utilizing the QTY code.

Through 250-nanosecond molecular dynamics simulations, we demonstrated that this altered complex preserves its essential helical topology and effectively binds the Amyloid Precursor Protein (APP). We successfully mapped critical residue level interactions, proving that substrate recognition remains intact outside a lipid environment. This establishes a new atomic level platform to evaluate substrate interactions in aqueous conditions, which is a critical step for advancing Alzheimer's disease drug discovery.

Karagöl, A., & Karagöl, T. (2025). Capture of Amyloid Precursor Protein Fragments by an Engineered Water-Soluble γ-Secretase Variant.

The full study is available here: https://doi.org/10.21203/rs.3.rs-8320072/v1