TY  - JOUR
AU  - Chen, Shu-Yu
AU  - Feilen, Lukas Peter
AU  - Chávez-Gutiérrez, Lucía
AU  - Steiner, Harald
AU  - Zacharias, Martin
TI  - Enzyme-substrate hybrid β-sheet controls geometry and water access to the γ-secretase active site.
JO  - Communications biology
VL  - 6
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DZNE-2023-00676
SP  - 670
PY  - 2023
AB  - γ-Secretase is an aspartyl intramembrane protease that cleaves the amyloid precursor protein (APP) involved in Alzheimer's disease pathology and other transmembrane proteins. Substrate-bound structures reveal a stable hybrid β-sheet immediately following the substrate scissile bond consisting of β1 and β2 from the enzyme and β3 from the substrate. Molecular dynamics simulations and enhanced sampling simulations demonstrate that the hybrid β-sheet stability is strongly correlated with the formation of a stable cleavage-compatible active geometry and it also controls water access to the active site. The hybrid β-sheet is only stable for substrates with 3 or more C-terminal residues beyond the scissile bond. The simulation model allowed us to predict the effect of Pro and Phe mutations that weaken the formation of the hybrid β-sheet which were confirmed by experimental testing. Our study provides a direct explanation why γ-secretase preferentially cleaves APP in steps of 3 residues and how the hybrid β-sheet facilitates γ-secretase proteolysis.
KW  - Amyloid Precursor Protein Secretases: genetics
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Catalytic Domain
KW  - Protein Conformation, beta-Strand
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Water Supply
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10290658
C6  - pmid:37355752
DO  - DOI:10.1038/s42003-023-05039-y
UR  - https://pub.dzne.de/record/258782
ER  -