4r12

Publication Abstract from PubMed

gamma-Secretase is an intramembrane protease responsible for the generation of amyloid-beta (Abeta) peptides. Aberrant accumulation of Abeta 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 gamma-secretase complex. No atomic-resolution structure had been identified on gamma-secretase or any of its four components, hindering mechanistic understanding of gamma-secretase function. Here we report the crystal structure of nicastrin from Dictyostelium purpureum at 1.95-A 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 gamma-secretase complex.

Crystal structure of the gamma-secretase component nicastrin.,Xie T, Yan C, Zhou R, Zhao Y, Sun L, Yang G, Lu P, Ma D, Shi Y Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13349-54. doi:, 10.1073/pnas.1414837111. Epub 2014 Sep 2. PMID:25197054^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.