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Processing of the β-amyloid precursor protein (βAPP) by β- and γ-secretases generates the amyloidogenic peptide Aβ, a major factor in the etiology of Alzheimer's disease. Following the recent identification of the β-secretase β-amyloid-converting enzyme (BACE), we herein investigate its zymogen processing, molecular properties, and cellular trafficking. Our data show that among the proprotein convertase family members, furin is the major converting enzyme of pro-BACE into BACE within the trans-Golgi network of HK293 cells. While we demonstrate that the 24-amino acid prosegment is required for the efficient exit of pro-BACE from the endoplasmic reticulum, it may not play a strong inhibitory role since we observe that pro-BACE can produce significant quantities of the Swedish mutant βAPP_sw β-secretase product C99. BACE is palmitoylated at three Cys residues within its transmembrane/cytosolic tail and is …