Crystal structure of the ?-secretase component nicastrin.

ABSTRACT: ?-Secretase is an intramembrane protease responsible for the generation of amyloid-? (A?) peptides. Aberrant accumulation of A? leads to the formation of amyloid plaques in the brain of patients with Alzheimer's disease. Nicastrin is the putative substrate-recruiting component of the ?-secretase complex. No atomic-resolution structure had been identified on ?-secretase or any of its four components, hindering mechanistic understanding of ?-secretase function. Here we report the crystal structure of nicastrin from Dictyostelium purpureum at 1.95-Å resolution. The extracellular domain of nicastrin contains a large lobe and a small lobe. The large lobe of nicastrin, thought to be responsible for substrate recognition, associates with the small lobe through a hydrophobic pivot at the center. The putative substrate-binding pocket is shielded from the small lobe by a lid, which blocks substrate entry. These structural features suggest a working model of nicastrin function. Analysis of nicastrin structure provides insights into the assembly and architecture of the ?-secretase complex.

SUBMITTER: Xie T 

PROVIDER: S-EPMC4169925 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature