Homodimerization of presenilin N-terminal fragments is affected by mutations linked to Alzheimer's disease.
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-gamma-secretase complex and that FAD mutations affect the assembly or stability of this complex.
Cervantes
S
S
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, 08028 Barcelona, Spain.
Gonzàlez-Duarte
R
R
Marfany
G
G
D000544:Alzheimer Disease / Q000235:genetics*; D019281:Dimerization; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1; D053766:Presenilin-2; D020798:Two-Hybrid System Techniques
D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; D005982:Glutathione Transferase