Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity.
Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity.
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DOI：
10.1371/journal.pone.0111553
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ran Y
中科院分区：
文献类型：
--
作者：
Jung JI;Premraj S;Cruz PE;Ladd TB;Kwak Y;Koo EH;Felsenstein KM;Golde TE;Ran Y
Altered production of β-amyloid (Aβ) 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 β-secretase derived APP carboxyl terminal fragment (CTFβ, C99) impairs processive cleavage by γ-secretase increasing production of long Aβs (e.g., Aβ1-42, 43). Other studies report that APP CTFβ 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 Aβ, was found to form SDS-stable APP dimers, once again suggesting a mechanistic link between dimerization and increased production of long Aβ. 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 Aβ 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 Aβ 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.
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DOI：
10.1186/alzrt121
发表时间：
2012-05-23
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Moore BD;Chakrabarty P;Levites Y;Kukar TL;Baine AM;Moroni T;Ladd TB;Das P;Dickson DW;Golde TE
通讯作者：
Golde TE
影响因子：
82.9
作者：
Kukar, T;Murphy, MP;Golde, TE
通讯作者：
Golde, TE
影响因子：
2.9
作者：
Kimberly, WT;Esler, WP;Wolfe, MS
通讯作者：
Wolfe, MS
影响因子：
4.8
作者：
Kienlen-Campard, Pascal;Tasiaux, Bernadette;Octave, Jean-Noel
通讯作者：
Octave, Jean-Noel
DOI：
10.1073/pnas.052436599
发表时间：
2002-03-05
影响因子：
11.1
作者：
Esler, WP;Kimberly, WT;Wolfe, MS
通讯作者：
Wolfe, MS