Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity.
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, C...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4211736?pdf=render |
| _version_ | 1818622094006550528 |
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| author | Joo In Jung Sasha Premraj Pedro E Cruz Thomas B Ladd Yewon Kwak Edward H Koo Kevin M Felsenstein Todd E Golde Yong Ran |
| author_facet | Joo In Jung Sasha Premraj Pedro E Cruz Thomas B Ladd Yewon Kwak Edward H Koo Kevin M Felsenstein Todd E Golde Yong Ran |
| author_sort | Joo In Jung |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T18:19:42Z |
| format | Article |
| id | doaj.art-8c31306f88694cd983907938974c274f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-16T18:19:42Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-8c31306f88694cd983907938974c274f2022-12-21T22:21:36ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01910e11155310.1371/journal.pone.0111553Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity.Joo In JungSasha PremrajPedro E CruzThomas B LaddYewon KwakEdward H KooKevin M FelsensteinTodd E GoldeYong RanAltered 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.http://europepmc.org/articles/PMC4211736?pdf=render |
| spellingShingle | Joo In Jung Sasha Premraj Pedro E Cruz Thomas B Ladd Yewon Kwak Edward H Koo Kevin M Felsenstein Todd E Golde Yong Ran Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity. PLoS ONE |
| title | Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity. |
| title_full | Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity. |
| title_fullStr | Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity. |
| title_full_unstemmed | Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity. |
| title_short | Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity. |
| title_sort | independent relationship between amyloid precursor protein app dimerization and γ secretase processivity |
| url | http://europepmc.org/articles/PMC4211736?pdf=render |
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