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

SPECIFIC AIMSTo identify the proprotein convertases responsible for maturation of the α-secretase ADAM10, we investigated the influence of PC7 and furin on ADAM10 processing and the resulting effect on amyloid precursor protein cleavage. We also examined the functional role of the ADAM10 prodomain by coexpression of a prodomain-deleted ADAM10 mutant together with its prodomain in trans.PRINCIPAL FINDINGS1. ADAM10 is proteolytically processed by PC7 and furinThe disintegrin metalloproteinase ADAM10 possesses α-secretase activity as well as a potential proprotein convertase recognition sequence (RKKR) after its prodomain. By amino-terminal sequencing of ADAM10 purified from bovine kidney plasma membranes, we recently showed that the proprotein convertase recognition sequence RKKR is used to generate the mature 62–64 kDa catalytically active form of ADAM10. Therefore, we investigated whether PC7 or furin might be proteinases that cleave the ADAM10 zymogen. To provide evidence for prodomain removal by these p...