Secretion of endothelin converting enzyme-1a: The hydrophobic signal anchor domain alone is not sufficient to promote membrane localization

Endothelin converting enzyme-1 (ECE-1) is a type II membrane protein that i s important for the proteolytic activation of big endothelin-1 to endotheli n-1. Although the highly conserved zinc-binding motif is known to be locate d in the extracellular domain, the role(s) of the N-terminal and membrane-s panning signal anchor domains in the biosynthesis and function of ECE-1 iso forms, ECE-1a, ECE-1b, and ECE-1c, remain undetermined. In this study, we p rovide evidence that the deletion of the cytoplasmic N-terminal tail (resid ues 1-55) of ECE-1a results in the cleavage of a potential signal peptide l ocated in the signal anchor domain leading to the partial secretion of the recombinant enzyme into the media. However, the truncation of N-terminal an d/or signal anchor domain does not affect the activity of ECE-1a. Therefore , our results demonstrate that the hydrophobic signal anchor domain alone i s not sufficient for the membrane anchoring of ECE-1a and that the N-termin al domain of ECE-1a is important for membrane targeting as well as the intr acellular localization of the enzyme.