Dimerization of presenilin-1 in vivo: suggestion of novel regulatory mechanisms leading to higher order complexes.
A growing body of evidence indicates that presenilins could exist and be active as oligomeric complexes. Using yeast two-hybrid and cell culture analysis, we provide evidence that presenilin-1 (PS1) may self-oligomerize giving rise to specific full-length/full-length homodimers. When expressed in N2A and HEK239T cultured cells, full-length PS1-wt and 5(')myc-PS1-wt form specific homodimers corresponding to twice their molecular weight. The Alzheimer's disease-associated PS1 mutations Y115H, M146L, L392V, deltaE10(PS1(1-289/320-467)), the gamma-secretase dominant negative mutant D257A, and the PS1 polymorphism mutant E318G do not affect their ability to self-oligomerize. Under non-denaturing conditions, endogenous PS1 forms specific homo-oligomers in human cultured cells. The results obtained herein suggest that PS1 associates intramolecularly to form higher order complexes, which may be needed for endoproteolytic cleavage and/or gamma-secretase-associated activity.
Hébert
Sébastien S
SS
Molecular and Human Genetics Unit, CHUQ-Pavillon St-François d'Assise, 10 rue de l' Espinay, Que., Canada G1L 3L5.
Godin
Chantal
C
Tomiyama
Takami
T
Mori
Hiroshi
H
Lévesque
Georges
G
D000818:Animals; D002460:Cell Line; D019281:Dimerization; D006801:Humans; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008970:Molecular Weight; D009154:Mutation; D053764:Presenilin-1; D020836:Protein Structure, Quaternary; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D046911:Macromolecular Substances; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1