Cryoelectron Microscopy Structure of Purified gamma-Secretase at 12 angstrom Resolution
{gamma}-Secretase, an integral membrane protein complex, catalyzes the intramembrane cleavage of the {beta}-amyloid precursor protein (APP) during the neuronal production of the amyloid {beta}-peptide. As such, the protease has emerged as a key target for developing agents to treat and prevent Alzheimer's disease. Existing biochemical studies conflict on the oligomeric assembly state of the protease complex, and its detailed structure is not known. Here, we report that purified active human {gamma}-secretase in digitonin has a total molecular mass of {approx} 230 kDa when measured by scanning transmission electron microscopy. This result supports a complex that is monomeric for each of the four component proteins. We further report the three-dimensional structure of the {gamma}-secretase complex at 12 {angstrom} resolution as obtained by cryoelectron microscopy and single-particle image reconstruction. The structure reveals several domains on the extracellular side, three solvent-accessible low-density cavities, and a potential substrate-binding surface groove in the transmembrane region of the complex.
- Research Organization:
- BROOKHAVEN NATIONAL LABORATORY (BNL)
- Sponsoring Organization:
- LABORATORY-DIRECTED RESEARCH AND DEVELOPMENT
- DOE Contract Number:
- AC02-98CH10886
- OSTI ID:
- 1040044
- Report Number(s):
- BNL--90082-2009-JA; YN0100000
- Journal Information:
- Journal of Molecular Biology, Journal Name: Journal of Molecular Biology Journal Issue: 2 Vol. 385; ISSN JMOBAK; ISSN 0022-2836
- Country of Publication:
- United States
- Language:
- English
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