Details

Autor(en) / Beteiligte

• Scheuermann, Stefan
• Hambsch, Boris
• Hesse, Lars
• Stumm, Joachim
• Schmidt, Carsten
• Beher, Dirk
• Bayer, Thomas A.
• Beyreuther, Konrad
• Multhaup, Gerd

Titel

Homodimerization of Amyloid Precursor Protein and Its Implication in the Amyloidogenic Pathway of Alzheimer's Disease

Ist Teil von

• The Journal of biological chemistry, 2001-09, Vol.276 (36), p.33923-33929

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2001

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• We reported previously that the carbohydrate domain of the amyloid precursor protein is involved in amyloid precursor protein (APP)-APP interactions. Functional in vitro studies suggested that this interaction occurs through the collagen binding site of APP. The physiological significance remained unknown, because it is not understood whether and how APP dimerization occurs in vivo. Here we report that cellular APP exists as homodimers matching best with a two-site model. Consistent with our published crystallographic data, we show that a deletion of the entire sequence after the kunitz protease inhibitor domain did not abolish APP homodimerization, suggesting that two domains are critically involved but that neither is essential for homodimerization. Finally, we generated stabilized dimers by expressing mutant APP with a single cysteine in the ectodomain juxtamembrane region. Mutation of Lys624 to cysteine produced ∼6–8-fold more Aβ than cells expressing normal APP. Our results suggest that amyloid Aβ production can in principle be positively regulated by dimerizationin vivo. We suggest that dimerization could be a physiologically important mechanism for regulating the proposed signal activity of APP.