TY - JOUR T1 - Mutagenesis of the ADAM17-phosphatidylserine–binding motif leads to embryonic lethality in mice JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900430 VL - 2 IS - 5 SP - e201900430 AU - Martin Veit AU - Björn Ahrens AU - Jana Seidel AU - Anselm Sommer AU - Sucharit Bhakdi AU - Karina Reiss Y1 - 2019/10/01 UR - https://www.life-science-alliance.org/content/2/5/e201900430.abstract N2 - ADAM17, prominent member of the “Disintegrin and Metalloproteinase” (ADAM) family, controls vital cellular functions through cleavage of transmembrane substrates. Several of these play central roles in oncogenesis and inflammation, yet despite its importance, the mechanism by which ADAM17 is activated is not fully understood. We recently presented evidence that surface exposure of phosphatidylserine (PS) is the penultimate event required for sheddase activation, which occurs upon binding of a membrane-proximal, cationic binding motif to the anionic phospholipid headgroup. Here, we show that mutagenesis of the 3 amino acids constituting the PS-binding motif leads to embryonic lethality in mice. Heterozygotes showed no abnormalities. Primary hepatocytes and fibroblasts were analysed and found to express the mutant protease on the cell surface. However, PMA-stimulated release of ADAM17 substrates was completely abolished. The results directly support the novel concept of transiently externalised PS as essential trigger of extracellular protease function in vivo. ER -