![]() ![]() NMR studies of two 14-mer peptides mimicking this region of the CT and its Ala variants revealed that the three exposed residues are on the same side of the molecule. Extensive CT deletions and mutagenesis analyses helped us zoom in on three residues in the CT, namely Glu-719, Glu-721, and Leu-725, that are part of a novel motif, E XE XXXL 725, critical for PC7 activity on hTfR1. Deletion of the TMCT resulted in soluble PC7 and loss of its hTfR1 shedding activity. To better understand the physiological roles of PC7, here we focused on the relationship between the CT-regulated trafficking of PC7 and its ability to shed hTfR1. PC7 sheds human transferrin receptor 1 (hTfR1) into soluble shTfR1 in endosomes. The seventh member, PC7, is a type-I transmembrane (TM) protein with a 97-residue–long cytosolic tail (CT). The proprotein convertases (PCs) form a family of nine secretory subtilisin-like serine proteases, seven of which cleave at specific basic residues within the trans-Golgi network, granules, or at the cell surface/endosomes. Many secretory proteins are activated by cleavage at specific sites.
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