Title : An atomic structure of human
γ-secretase
Abstract :
- Dysfunction of the intramembrane protea se γ-secretase is thought to cau se Alzheimer 's disea se , with most mutations derived from Alzheimer's disea se mapping to the catalytic subunit presenilin 1 ( PS1 )
- Here we report an atomic structure of human γ-secretase at 3 .4 Å resolution, determined by single-particle cryo-electron microscopy
- Mutations derived from Alzheimer's di se a se affect residues at two hotspots in PS1 , each located at the centre of a distinct four transmembrane segment (TM) bundle
- TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements
- The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment
- Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1
- Ordered phospholipids stabilize the complex inside the membrane
- Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function