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

Ectodomain shedding of the Alzheimer's amyloid precursor protein is mediated by alpha- and beta -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 alpha -secretase activity of ADAM10. Overexpression of the proprotein convertases PC7 and furin in human embryonic kidney 293 cells revealed an increased ADAM10 maturation resulting in enhanced alpha -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 alpha -secretase activity of wild-type ADAM10. However, the prodomain acted as a chaperone and functionally rescued the alpha -secretase activity of a former inactive ADAM10 mutant lacking the prodomain. The results of our study suggest new approaches to enhance the nonamyloidogenic alpha -secretase pathway.