4R12

Crystal structure of the gamma-secretase component Nicastrin

Summary for 4R12

• Entry DOI: 10.2210/pdb4r12/pdb
• Descriptor: Putative uncharacterized protein, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: alpha/beta, nicastrin, putative substrate-recruiting component, gamma-secretase complex, protein binding
• Biological source: Dictyostelium purpureum (Slime mold)
• Total number of polymer chains: 1
• Total formula weight: 68440.68

Authors

Xie, T.,Yan, C.,Zhou, R.,Zhao, Y.,Sun, L.,Yang, G.,Lu, P.,Ma, D.,Shi, Y. (deposition date: 2014-08-03, release date: 2014-09-17, Last modification date: 2024-11-13)

Primary citation

Xie, T.,Yan, C.,Zhou, R.,Zhao, Y.,Sun, L.,Yang, G.,Lu, P.,Ma, D.,Shi, Y.
Crystal structure of the gamma-secretase component nicastrin.
Proc.Natl.Acad.Sci.USA, 111:13349-13354, 2014

PubMed Abstract: γ-Secretase is an intramembrane protease responsible for the generation of amyloid-β (Aβ) peptides. Aberrant accumulation of Aβ 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 γ-secretase complex. No atomic-resolution structure had been identified on γ-secretase or any of its four components, hindering mechanistic understanding of γ-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 γ-secretase complex.

PubMed: 25197054
DOI: 10.1073/pnas.1414837111

Experimental method

X-RAY DIFFRACTION (1.95 Å)