The disulphide bonds in the catalytic domain of BACE are critical but not essential for amyloid precursor protein processing activity

β‐Site APP‐cleaving enzyme (BACE) initiates the processing of the amyloid precursor protein (APP) leading to the generation of β‐amyloid, the main component of Alzheimer's disease senile plaques. BACE (Asp2, memapsin 2) is a type I transmembrane aspartic protease responsible for the β‐secretase cleavage of APP producing a soluble form of the ectodomain (sAPPβ) and the membrane‐bound, carboxy‐terminal intermediates C99 and C89. BACE maturation involves cysteine bridge formation, N‐glycosylation and propeptide removal. We investigated variants of BACE in which the disulphide bonds of the catalytic domain spanning between Cys216/Cys420, Cys278/Cys443 and Cys330/Cys380 were removed by mutagenesis. When transfected in cultured cells, these mutants showed impaired maturation. Nevertheless, a fraction of mutated protein retained both the competence to mature as well as the activity to process APP. For the generation of a functional enzyme the conserved Cys330/Cys380 bond was the most critical, whereas the two bonds between Cys216/Cys420 and Cys278/Cys443, which are typical for the membrane‐bound BACE, appeared to be less important.