Mechanism of intramembrane cleavage of alcadeins by γ-secretase.

<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). A...

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Autores principales:	Yi Piao, Ayano Kimura, Satomi Urano, Yuhki Saito, Hidenori Taru, Tohru Yamamoto, Saori Hata, Toshiharu Suzuki
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d837907de24f4ed784ec9c3f5f58eae3
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spelling	oai:doaj.org-article:d837907de24f4ed784ec9c3f5f58eae32021-11-18T07:47:40ZMechanism of intramembrane cleavage of alcadeins by γ-secretase.1932-620310.1371/journal.pone.0062431https://doaj.org/article/d837907de24f4ed784ec9c3f5f58eae32013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23658629/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<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 to release the intracellular domain fragment (AICD) and consequently the γ-site is determined, by which Aβ generates. The initial ε-site is thought to define the final γ-site position, which determines whether Aβ40/43 or Aβ42 is generated. However, initial intracellular ε-cleavage sites of Alc CTF to generate Alc ICD and the molecular mechanism that final γ-site position is determined remains unclear in Alcs.<h4>Methodology</h4>Using HEK293 cells expressing Alcs plus presenilin 1 (PS1, a catalytic unit of γ-secretase) and the membrane fractions of these cells, the generation of p3-Alc possessing C-terminal γ-cleavage site and Alc ICD possessing N-terminal ε-cleavage site were analysed with MALDI-TOF/MS. We determined the initial ε-site position of all Alcα, Alcβ and Alcγ, and analyzed the relationship between the initially determined ε-site position and the final γ-cleavage position.<h4>Conclusions</h4>The initial ε-site position does not always determine the final γ-cleavage position in Alcs, which differed from APP. No additional γ-cleavage sites are generated from artificial/non-physiological positions of ε-cleavage for Alcs, while the artificial ε-cleavage positions can influence in selection of physiological γ-site positions. Because alteration of γ-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 γ-secretase, which may be induced by malfunction of γ-secretase itself or changes of membrane environment for enzymatic reaction.Yi PiaoAyano KimuraSatomi UranoYuhki SaitoHidenori TaruTohru YamamotoSaori HataToshiharu SuzukiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e62431 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yi Piao Ayano Kimura Satomi Urano Yuhki Saito Hidenori Taru Tohru Yamamoto Saori Hata Toshiharu Suzuki Mechanism of intramembrane cleavage of alcadeins by γ-secretase.
description	<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 to release the intracellular domain fragment (AICD) and consequently the γ-site is determined, by which Aβ generates. The initial ε-site is thought to define the final γ-site position, which determines whether Aβ40/43 or Aβ42 is generated. However, initial intracellular ε-cleavage sites of Alc CTF to generate Alc ICD and the molecular mechanism that final γ-site position is determined remains unclear in Alcs.<h4>Methodology</h4>Using HEK293 cells expressing Alcs plus presenilin 1 (PS1, a catalytic unit of γ-secretase) and the membrane fractions of these cells, the generation of p3-Alc possessing C-terminal γ-cleavage site and Alc ICD possessing N-terminal ε-cleavage site were analysed with MALDI-TOF/MS. We determined the initial ε-site position of all Alcα, Alcβ and Alcγ, and analyzed the relationship between the initially determined ε-site position and the final γ-cleavage position.<h4>Conclusions</h4>The initial ε-site position does not always determine the final γ-cleavage position in Alcs, which differed from APP. No additional γ-cleavage sites are generated from artificial/non-physiological positions of ε-cleavage for Alcs, while the artificial ε-cleavage positions can influence in selection of physiological γ-site positions. Because alteration of γ-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 γ-secretase, which may be induced by malfunction of γ-secretase itself or changes of membrane environment for enzymatic reaction.
format	article
author	Yi Piao Ayano Kimura Satomi Urano Yuhki Saito Hidenori Taru Tohru Yamamoto Saori Hata Toshiharu Suzuki
author_facet	Yi Piao Ayano Kimura Satomi Urano Yuhki Saito Hidenori Taru Tohru Yamamoto Saori Hata Toshiharu Suzuki
author_sort	Yi Piao
title	Mechanism of intramembrane cleavage of alcadeins by γ-secretase.
title_short	Mechanism of intramembrane cleavage of alcadeins by γ-secretase.
title_full	Mechanism of intramembrane cleavage of alcadeins by γ-secretase.
title_fullStr	Mechanism of intramembrane cleavage of alcadeins by γ-secretase.
title_full_unstemmed	Mechanism of intramembrane cleavage of alcadeins by γ-secretase.
title_sort	mechanism of intramembrane cleavage of alcadeins by γ-secretase.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/d837907de24f4ed784ec9c3f5f58eae3
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_version_	1718422939953528832

Mechanism of intramembrane cleavage of alcadeins by γ-secretase.

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