Dimerization of presenilin-1 in vivo: suggestion of novel regulatory mechanisms leading to higher order complexes.

Molecular and Human Genetics Unit, CHUQ-Pavillon St-Francois d'Assise, 10 rue de l' Espinay, Que., Canada G1L 3L5.
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.
Mesh Terms:
Animals, Cell Line, Dimerization, Humans, Macromolecular Substances, Membrane Proteins, Mice, Molecular Weight, Mutation, Presenilin-1, Protein Structure, Quaternary, Saccharomyces cerevisiae, Two-Hybrid System Techniques
Biochem. Biophys. Res. Commun. Jan. 31, 2003; 301(1);119-26 [PUBMED:12535650]
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