Document Detail


Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution.
MedLine Citation:
PMID:  19013469     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Pamela Osenkowski; Hua Li; Wenjuan Ye; Dongyang Li; Lorene Aeschbach; Patrick C Fraering; Michael S Wolfe; Dennis J Selkoe; Huilin Li
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2008-11-05
Journal Detail:
Title:  Journal of molecular biology     Volume:  385     ISSN:  1089-8638     ISO Abbreviation:  J. Mol. Biol.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-09     Completed Date:  2009-02-03     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  2985088R     Medline TA:  J Mol Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  642-52     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amyloid Precursor Protein Secretases / chemistry,  ultrastructure*
Binding Sites
Cryoelectron Microscopy*
Humans
Image Processing, Computer-Assisted
Microscopy, Electron, Scanning
Models, Molecular
Molecular Weight
Protein Structure, Quaternary
Protein Structure, Tertiary
Protein Subunits
Grant Support
ID/Acronym/Agency:
P01 AG015379/AG/NIA NIH HHS; P01 AG015379-09/AG/NIA NIH HHS; P01 AG15379/AG/NIA NIH HHS; R01 GM74985/GM/NIGMS NIH HHS; TE AG00222-15/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Protein Subunits; EC 3.4.-/Amyloid Precursor Protein Secretases
Comments/Corrections

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