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Regulation of the α‐secretase ADAM10 by its prodomain and proprotein convertases

Ectodomain shedding of the Alzheimer's amyloid precursor protein is mediated by α‐ and β‐secretases, which, for their part, are also proteolytically processed. The disintegrin metalloproteinase ADAM10 is synthesized as a zymogen with a proprotein convertase (PC) recognition sequence between the prodomain and the catalytic domain. In this study, we investigated the role of the prodomain in the regulation of the α‐secretase activity of ADAM 10. Overexpression of the proprotein convertases PC7 and furin in human embryonic kidney 293 cells revealed an increased ADAM10 maturation resulting in enhanced α‐secretase‐mediated processing of amyloid precursor protein. Mutation of the PC recognition sequence in ADAM10 as well as the use of a PC inhibitor and of the furin‐deficient LoVo cell line confirmed the role of PCs, in particular, of PC7, in ADAM10 maturation and activation. Furthermore, we demonstrated that the prodomain of ADAM10 has a dual function. When coexpressed in trans as separate polypeptide, it inhibited the α‐secretase activity of wild‐type ADAM10. However, the prodomain acted as a chaperone and functionally rescued the α‐secretase activity of a former inactive ADAM10 mutant lacking the prodomain. The results of our study suggest new approaches to enhance the nonamyloidogenic α‐secretase pathway.