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Homodimerization of presenilin N‐terminal fragments is affected by mutations linked to Alzheimer's disease
Author(s) -
Cervantes Sara,
Gonzàlez-Duarte Roser,
Marfany Gemma
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)02785-5
Subject(s) - presenilin , endoplasmic reticulum , transmembrane protein , microbiology and biotechnology , mutation , biochemistry , biology , chemistry , alzheimer's disease , receptor , gene , disease , medicine , pathology
Mutations on human presenilins 1 and 2 cause dominant early‐onset familial Alzheimer's disease (FAD). Presenilins are polytopic transmembrane proteins endoproteolytically processed in vivo to N‐ and C‐terminal fragments (NTFs and CTFs). The functional presenilin unit consists of a high molecular weight complex that contains both fragments. Here we show NTF:NTF, CTF:CTF and NTF:CTF interactions by yeast two‐hybrid and in vivo endoplasmic reticulum split‐ubiquitin assays. Our results also highlight the involvement of HL1 – the hydrophilic loop between TMI and TMII – in the NTF:NTF binding site. Besides, nine FAD‐linked presenilin mutations substantially affected HL1:HL1 binding. From the evidence of NTF and CTF homodimerization, we propose the contribution of two NTFs and two CTFs, instead of a single NTF:CTF heterodimer, to the functional presenilin–γ‐secretase complex and that FAD mutations affect the assembly or stability of this complex.