POST-TRANSLATIONAL PROCESSING OF .BETA.-SECRETASE (BACE): THE PRO-AND TRANSMEMBRANE/CYTOSOLIC DOMAINS AFFECT ITS CELLULAR ACTIVITY AND AMYLOID A.BETA. PRODUCTION

摘要

Processing of the .beta.-amyloid precursor .beta.APP by .beta.- and .gamma.- secetases generates the amyloidogenic peptide A.beta., which has been implicated as a major factor i n the etiology of Alzheimer's disease. The recent identification of BACE as a candidate .beta.- secretase prompted us to investigate the zymogen processing of proBACE and i ts molecular and cellular trafficking. Our data suggest that furin is the major proprotein convertase responsible for the conversion of proBACE into BACE within the traps Golgi network. While removal of the 24 as prosegment is required i n order for BACE to achieve its maximal catalytic activity in vitro, we provide evidence that proBACE can produce significant quantities of the Swedish mutant .beta.APP s w .beta.- secretase product C99. BACE is palmitoylated at three Cys residues within it s transmembrane/cytosolic tail and is sulfated at mature N-glycosylated moieties. Overexpression of full-length BALE in HK293 cells causes a significant increase in the production of C99 and a decrease in the production of the .alpha.- secretase product APPs.alpha.. Although there was little increase in the generation of A.beta. by full-length BACE, overexpression of either a soluble form of BACE or a form lacking t he prosegment lead to a significant increase in A.beta.levels, supporting the hypothesis that mislocalization of BACE can be a major factor in the amyloidogenic processin g of .beta.APP.