| Effects of membrane lipids on the activity and processivity of purified γ-secretase. | |
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MedLine Citation:
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PMID: 22489600 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The 19-transmembrane multisubunit γ-secretase complex generates the amyloid β-peptide (Aβ) of Alzheimer's disease (AD) by intramembrane proteolysis of the β-amyloid precursor protein (APP). Despite substantial advances in elucidating how this protein complex functions, the effect of the local membrane lipid microenvironment on γ-secretase cleavage of substrates is still poorly understood. Using detergent-free proteoliposomes to reconstitute purified human γ-secretase, we examined the effects of fatty acyl (FA) chain length, saturation and double-bond isomerization, and membrane lipid polar headgroups on γ-secretase function. We analyzed γ-secretase activity and processivity [i.e., sequential cleavages in the APP transmembrane domain that convert longer Aβ species (e.g., Aβ(46)) into shorter ones (e.g., Aβ(40))] by quantifying the APP intracellular domain (AICD) and various Aβ peptides, including via a bicine/urea gel system that detects multiple Aβ lengths. These assays revealed several trends. (1) Switching from a cis to a trans isomer of a monounsaturated FA chain in phosphatidylcholine (PC) increased γ-activity, did not affect Aβ(42):Aβ(40) ratios, but decreased the ratio of long (≥42) versus short (≤41) Aβ peptides. (2) Increasing the FA carbon chain length (14, 16, 18, and 20) increased γ-activity, reduced longer Aβ species, and reduced the Aβ(42):Aβ(40) ratio. (3) Shifting the position of the double bond in 18:1(Δ9-cis) PC to the Δ6 position substantially reduced activity. (4) Gangliosides increased γ-activity but decreased processivity, thus elevating the Aβ(42):Aβ(40) ratio. (5) Phosphatidylserine decreased γ-activity but increased processivity. (6) Phosphatidylinositol strongly inhibited γ-activity. Overall, our results show that subtle changes in membrane lipid composition can greatly influence γ-secretase activity and processivity, suggesting that relatively small changes in lipid membrane composition may affect the risk of AD at least as much as presenilin or APP mutations do. |
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Authors:
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Oliver Holmes; Swetha Paturi; Wenjuan Ye; Michael S Wolfe; Dennis J Selkoe |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-04-19 |
Journal Detail:
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Title: Biochemistry Volume: 51 ISSN: 1520-4995 ISO Abbreviation: Biochemistry Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-05-01 Completed Date: 2012-06-25 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 0370623 Medline TA: Biochemistry Country: United States |
Other Details:
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Languages: eng Pagination: 3565-75 Citation Subset: IM |
Affiliation:
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Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, United States. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amyloid Precursor Protein Secretases
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isolation & purification*,
metabolism* Amyloid beta-Peptides / chemistry, metabolism Animals CHO Cells Cricetinae Enzyme Activation Fatty Acids / chemistry Humans Lipid Bilayers / chemistry Membrane Lipids / chemistry*, metabolism Peptide Fragments / chemistry, metabolism Protein Processing, Post-Translational* Proteolysis Substrate Specificity |
| Grant Support | |
ID/Acronym/Agency:
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P01 AG015379/AG/NIA NIH HHS; P01 AG015379/AG/NIA NIH HHS; P01 AG015379-14/AG/NIA NIH HHS; R01 AG006173/AG/NIA NIH HHS; R01 AG012749/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Peptides; 0/Fatty Acids; 0/Lipid Bilayers; 0/Membrane Lipids; 0/Peptide Fragments; 0/amyloid beta-protein (1-40); 0/amyloid beta-protein (40-42); EC 3.4.-/Amyloid Precursor Protein Secretases |
| Comments/Corrections | |
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