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Pen‐2 is dispensable for endoproteolysis of presenilin 1, and nicastrin‐Aph subcomplex is important for both γ‐secretase assembly and substrate recruitment
Author(s) -
Mao Guozhang,
Cui MeiZhen,
Li Tong,
Jin Yipeng,
Xu Xuemin
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12016
Subject(s) - nicastrin , presenilin , gene knockdown , amyloid precursor protein , microbiology and biotechnology , biology , cleavage (geology) , chemistry , biochemistry , alzheimer's disease , medicine , apoptosis , disease , paleontology , fracture (geology)
γ‐secretase is a protease complex with at least four components: presenilin, nicastrin ( NCT ), anterior pharynx‐defective 1 (Aph‐1), and presenilin enhancer 2 (Pen‐2). In this study, using knockout cell lines and small interfering RNA technology, our data demonstrated that the disappeared presenilin 1 C‐terminal fragment ( PS 1C) caused by knockdown of pen‐2 or knockout of NCT or Aph‐1 was recovered by the addition of proteasome inhibitors, indicating that Pen‐2, as well as NCT and Aph‐1α, is dispensable for presenilin endoproteolysis. Our data also demonstrate that the formation of the nicastrin‐Aph‐1 subcomplex plays not only an important role in γ‐secretase complex assembly but also in recruiting substrate C‐terminal fragment of amyloid precursor protein generated by β‐cleavage. Ablating any one component resulted in the instability of other components of the γ‐secretase complex, and the presence of all three of the other components is required for full maturation of NCT .