Dataset Information
Mechanism of intramembrane cleavage of alcadeins by ?-secretase.
Ontology highlight
ABSTRACT: Background
Alcadein proteins (Alcs; Alc?, Alc?and Alc?) are predominantly expressed in neurons, as is Alzheimer's ?-amyloid (A?) precursor protein (APP). Both Alcs and APP are cleaved by primary ?- or ?-secretase to generate membrane-associated C-terminal fragments (CTFs). Alc CTFs are further cleaved by ?-secretase to secrete p3-Alc peptide along with the release of intracellular domain fragment (Alc ICD) from the membrane. In the case of APP, APP CTF? is initially cleaved at the ?-site to release the intracellular domain fragment (AICD) and consequently the ?-site is determined, by which A? generates. The initial ?-site is thought to define the final ?-site position, which determines whether A?40/43 or A?42 is generated. However, initial intracellular ?-cleavage sites of Alc CTF to generate Alc ICD and the molecular mechanism that final ?-site position is determined remains unclear in Alcs.Methodology
Using HEK293 cells expressing Alcs plus presenilin 1 (PS1, a catalytic unit of ?-secretase) and the membrane fractions of these cells, the generation of p3-Alc possessing C-terminal ?-cleavage site and Alc ICD possessing N-terminal ?-cleavage site were analysed with MALDI-TOF/MS. We determined the initial ?-site position of all Alc?, Alc? and Alc?, and analyzed the relationship between the initially determined ?-site position and the final ?-cleavage position.Conclusions
The initial ?-site position does not always determine the final ?-cleavage position in Alcs, which differed from APP. No additional ?-cleavage sites are generated from artificial/non-physiological positions of ?-cleavage for Alcs, while the artificial ?-cleavage positions can influence in selection of physiological ?-site positions. Because alteration of ?-secretase activity is thought to be a pathogenesis of sporadic Alzheimer's disease, Alcs are useful and sensitive substrate to detect the altered cleavage of substrates by ?-secretase, which may be induced by malfunction of ?-secretase itself or changes of membrane environment for enzymatic reaction.
SUBMITTER: Piao Y
PROVIDER: S-EPMC3637299 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
Mechanism of intramembrane cleavage of alcadeins by γ-secretase.
PloS one 20130426 4
<h4>Background</h4>Alcadein proteins (Alcs; Alcα, Alcβand Alcγ) are predominantly expressed in neurons, as is Alzheimer's β-amyloid (Aβ) precursor protein (APP). Both Alcs and APP are cleaved by primary α- or β-secretase to generate membrane-associated C-terminal fragments (CTFs). Alc CTFs are further cleaved by γ-secretase to secrete p3-Alc peptide along with the release of intracellular domain fragment (Alc ICD) from the membrane. In the case of APP, APP CTFβ is initially cleaved at the ε-site ...[more]