PMID: 26280335

 

    Legend: Sugar

Title : An atomic structure of human γ-secretase

Abstract :
  1. 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 )
  2. Here we report an atomic structure of human γ-secretase at 3 .4 Å resolution, determined by single-particle cryo-electron microscopy
  3. 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
  4. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements
  5. 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
  6. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1
  7. Ordered phospholipids stabilize the complex inside the membrane
  8. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function