Research article summary (published 12 Oct 2009):

gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment.

Full Abstract

Amyloid beta protein (Abeta), a pathogenic molecule associated with Alzheimer's disease, is produced by gamma-secretase, which cleaves the beta-carboxyl terminal fragment (betaCTF) of beta-amyloid precursor protein in the middle of its transmembrane domain. How the cleavage proceeds within the membrane has long been enigmatic. We hypothesized previously that betaCTF is cleaved first at the membrane-cytoplasm boundary, producing two long Abetas, Abeta(48) and Abeta(49), which are processed further by releasing three residues at each step to produce Abeta(42) and Abeta(40), respectively. To test this hypothesis, we used liquid chromatography tandem mass spectrometry (LC-MS/MS) to quantify the specific tripeptides that are postulated to be released. Using CHAPSO (3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxyl-1-propanesulfonate)-reconstituted gamma-secretase system, we confirmed that Abeta(49) is converted to Abeta(43/40) by successively releasing two or three tripeptides and that Abeta(48) is converted to Abeta(42/38) by successively releasing two tripeptides or these plus an additional tetrapeptide. Most unexpectedly, LC-MS/MS quantification revealed an induction period, 3-4 min, in the generation of peptides. When extrapolated, each time line for each tripeptide appears to intercept the same point on the x-axis. According to numerical simulation based on the successive reaction kinetics, the induction period exists. These results strongly suggest that Abeta is generated through the stepwise processing of betaCTF by gamma-secretase.

Author information

Author/s: Takami, Mako (M); Nagashima, Yu (Y); Sano, Yoshihisa (Y); Ishihara, Seiko (S); Morishima-Kawashima, Maho (M); Funamoto, Satoru (S); Ihara, Yasuo (Y);

Affiliation: Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kizugawa 619-0225, Japan.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci), published in United States. (Language: eng)

Reference: 2009-Oct; vol 29 (issue 41) : pp 13042-52

Dates: Created 2009/10/15; Completed 2009/10/30;

PMID: 19828817, status: MEDLINE (last retrieval date: 10/30/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

External Links for this article
(including full text providers, if available):

Click Electronic Full-text Provider Links to see options for finding the electronic full text links to this article. Note there may be a subscription or fee required for access to the full text. See our FAQ for information on finding FREE full text articles.

This article may also be located in paper journal collections available in many libraries. Use the Journal and Publication Information above to find the full article.

MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Amyloid Precursor Protein Secretases - physiology Amyloid beta-Protein - chemistry; metabolism Amyloid beta-Protein Precursor - chemistry; metabolism Analysis of Variance Animals CHO Cells - ultrastructure Cell Membrane - drug effects; metabolism Cholic Acids - pharmacology Chromatography, Liquid - methods Cricetinae

Cricetulus Detergents - pharmacology Immunoprecipitation - methods Models, Biological Oligopeptides - chemistry; metabolism Peptide Fragments - analysis; metabolism Protein Structure, Tertiary - physiology Substrate Specificity Tandem Mass Spectrometry - methods Time Factors

Associated Chemicals: Amyloid beta-Protein (0) ; Amyloid beta-Protein Precursor (0) ; Cholic Acids (0) ; Detergents (0) ; Oligopeptides (0) ; Peptide Fragments (0) ; chapso (82473-24-3) ; Amyloid Precursor Protein Secretases (EC 3.4.-)

Related articles

These are the highest related articles currently in the database:

• Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. 26 Sep 2004
• [Amyloid-beta 42 generating process may have a biological role in regulation of Notch signaling intensity] 30 Oct 2008
• FAD-linked mutations in presenilin 1 alter the length of Abeta peptides derived from betaAPP transmembrane domain mutants. 14 Mar 2002
• A novel gamma -secretase assay based on detection of the putative C-terminal fragment-gamma of amyloid beta protein precursor. 3 Jan 2001
• BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. 31 Oct 2006
• Human beta-secretase (BACE) and BACE inhibitors: progress report. 30 Dec 2005
• [Study on expression of PS1 in APP-PS1 double gene stably transfected cell lines and its relation to gamma-secretase] 29 Apr 2005
• Games played by rogue proteins in prion disorders and Alzheimer's disease. 29 Oct 2003
• Effects of gamma-secretase cleavage-region mutations on APP processing and Abeta formation: interpretation with sequential cleavage and alpha-helical model. 18 Sep 2008
• Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta-protein generation. 30 Jul 2000

See 100+ related articles.

Related Article Map

Legend: - FREE Full text Article. - Abstract only. - Title only. More help.

See a large map of 100+ related articles.