Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity.
PLoS One
; 9(10): e111553, 2014.
Article
in En
| MEDLINE
| ID: mdl-25350374
ABSTRACT
Altered production of ß-amyloid (Aß) from the amyloid precursor protein (APP) is closely associated with Alzheimer's disease (AD). APP has a number of homo- and hetero-dimerizing domains, and studies have suggested that dimerization of ß-secretase derived APP carboxyl terminal fragment (CTFß, C99) impairs processive cleavage by γ-secretase increasing production of long Aßs (e.g., Aß1-42, 43). Other studies report that APP CTFß dimers are not γ-secretase substrates. We revisited this issue due to observations made with an artificial APP mutant referred to as 3xK-APP, which contains three lysine residues at the border of the APP ectodomain and transmembrane domain (TMD). This mutant, which dramatically increases production of long Aß, was found to form SDS-stable APP dimers, once again suggesting a mechanistic link between dimerization and increased production of long Aß. To further evaluate how multimerization of substrate affects both initial γ-secretase cleavage and subsequent processivity, we generated recombinant wild type- (WT) and 3xK-C100 substrates, isolated monomeric, dimeric and trimeric forms of these proteins, and evaluated both ε-cleavage site utilization and Aß production. These show that multimerization significantly impedes γ-secretase cleavage, irrespective of substrate sequence. Further, the monomeric form of the 3xK-C100 mutant increased long Aß production without altering the initial ε-cleavage utilization. These data confirm and extend previous studies showing that dimeric substrates are not efficient γ-secretase substrates, and demonstrate that primary sequence determinants within APP substrate alter γ-secretase processivity.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Amyloid beta-Protein Precursor
/
Amyloid Precursor Protein Secretases
Limits:
Animals
Language:
En
Journal:
PLoS One
Journal subject:
CIENCIA
/
MEDICINA
Year:
2014
Document type:
Article