Human sorCS1 binds sortilin and hampers its cellular functions

Sortilin and sorCS1, both members of the Vps10p-D receptor family, are synthesized as precursor proteins and are converted to their mature form by enzymatic cleavage of a short N-terminal propeptide. SorCS1 does not bind its propeptide, but sortilin is able to bind not just its own propeptide but also that of sorCS1. Here we show that the propeptide region of sorCS1 contains two separate sites for binding to sortilin and that only one of these sites is removed from human (as opposed to mouse) sorCS1 during processing. This leaves mature human sorCS1 with a sortilin-binding N-terminus, which allows complex formation between the two receptors in solution and on cell membranes. Furthermore, we find that the interaction with sorCS1 has a pronounced effect on sortilins ability to mediate cellular uptake of alternative ligands, and to hamper its facilitation of CNTF signaling and induction of phosphorylated STAT3. Thus, the present findings reveal a novel regulatory mechanism and suggest an entirely new role of sorCS1 as a modulator of sortilin function.

Source: BJ Cell - October 16, 2013 Category: Biochemistry Authors: J Vejby Larsen, G Hermey, E Skipper Sørensen, T Prabakaran, E Ilsø Christensen, J Gliemann, P Madsen, C Munck Petersen Tags: BJ Cell Source Type: research