RT Journal Article
SR Electronic
T1 Mutagenesis of the ADAM17-phosphatidylserine–binding motif leads to embryonic lethality in mice
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900430
DO 10.26508/lsa.201900430
VO 2
IS 5
A1 Martin Veit
A1 Björn Ahrens
A1 Jana Seidel
A1 Anselm Sommer
A1 Sucharit Bhakdi
A1 Karina Reiss
YR 2019
UL https://www.life-science-alliance.org/content/2/5/e201900430.abstract
AB 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.