Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
J Mol Biol. 2009 Jan 16;385(2):642-52. doi: 10.1016/j.jmb.2008.10.078. Epub 2008 Nov 5.

Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution.

Author information

  • 1Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.

Abstract

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 approximately 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 A 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.

PMID:
19013469
[PubMed - indexed for MEDLINE]
PMCID:
PMC2830092
Free PMC Article

Images from this publication.See all images (6)Free text

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk