A mono phenylalanine-based motif (F-790) and a leucine-dependent motif (LI760) mediate internalization of furin

The eukaryotic endoprotease furin, a member of the subtilisin-related famil y of prohormone convertases, is synthesized and transported within the cons titutive secretory pathway to the plasma membrane, from where it recycles t o the trans-Golgi network (TGN). Previous studies showed that TGN-residence and recycling are mediated by the cytoplasmic tail. Two targeting determin ants have been described so far, the acidic signal CPSDSEEDEG783 containing two casein kinase II (CKII) phosphorylation sites and the internalization signal YKGL765. Refined analyses of the cytoplasmic domain of furin, which was mutagenized and tagged to the influenza hemagglutinin and to the membra ne cofactor protein (CD46) as reporter molecules reveal two additional inte rnalization determinants, a leucine-isoleucine signal, LI760, and a mono ph enylalanine-based motif at F-790, which functions without any specific neig hboring amino acid sequence. Both signals are capable of independently medi ating internalization, as has been shown previously for the tyrosine-based signal. Thus, furin internalization is mediated by at least three independe nt endocytosis signals.