Proteasome inhibitors induce the association of Alzheimer's amyloid precursor protein with Hsc73

Amyloid precursor protein (APP) is a secretory membrane-bound protein that undergoes restrictive proteolysis and degradation with a short life span in the constitutive secretory pathway or in the endosomal/ lysosomal compartm ent. The degradation machinery, including cellular trafficking and the rest rictive cleavage of APP, is poorly understood. To gain further insight into the intracellular degradation mechanism of APP, we searched for effector p roteins that interact with APP. We found that a cytosolic molecular chapero n, Hsc73, effectively interacts with the cytoplasmic domain of APP in the p resence of proteasome inhibitors. Hsc73 binds to the cytoplasmic domain nea r the post-transmembrane region of APP and not to the KFERQ-related sequenc e, KFFEQ, at the C-terminal tail that is assumed to be the selective target ing signal for lysosomal proteolysis. The amounts of Hsc73 that bind to sev eral APP species such as those found in pathological Familial Alzheimer's d isease (FAD), Swedish, or Dutch type mutation, are almost identical, sugges ting that an abnormal conformation around the secretory cleavage site or a pathological imbalance in APP processing are not irrelevant to the efficien cy of Hsc73 binding. (C) 1999 Academic Press.