Human sorCS1 binds sortilin and hampers its cellular functions

TY - JOUR

T1 - Human sorCS1 binds sortilin and hampers its cellular functions

AU - Larsen, Jakob Vejby

AU - Hermey, Guido

AU - Sørensen, Esben Skipper

AU - Prabakaran, Thaneas

AU - Christensen, Erik Ilsø

AU - Gliemann, Jørgen

AU - Madsen, Peder

AU - Petersen, Claus Munck

PY - 2014/1/15

Y1 - 2014/1/15

N2 - Sortilin and sorCS1 [sortilin-related Vps10p (vacuolar protein sorting/targeting protein 10) domain-containing receptor 1], both members of the Vps10p-D (Vps10p-domain) receptor family, are synthesized as precursor proteins and are converted into 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. In the present study 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 formation of a complex between the two receptors in solution and on cell membranes. Furthermore, we find that the interaction with sorCS1 has a pronounced effect on sortilin's ability to mediate the cellular uptake of alternative ligands, and to hamper its facilitation of CNTF (ciliary neutrophic factor) signalling and the induction of phosphorylated STAT3 (signal transducer and activator of transcription 3). Thus the present study reveals a novel regulatory mechanism and suggest an entirely new role for sorCS1 as a modulator of sortilin function.

AB - Sortilin and sorCS1 [sortilin-related Vps10p (vacuolar protein sorting/targeting protein 10) domain-containing receptor 1], both members of the Vps10p-D (Vps10p-domain) receptor family, are synthesized as precursor proteins and are converted into 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. In the present study 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 formation of a complex between the two receptors in solution and on cell membranes. Furthermore, we find that the interaction with sorCS1 has a pronounced effect on sortilin's ability to mediate the cellular uptake of alternative ligands, and to hamper its facilitation of CNTF (ciliary neutrophic factor) signalling and the induction of phosphorylated STAT3 (signal transducer and activator of transcription 3). Thus the present study reveals a novel regulatory mechanism and suggest an entirely new role for sorCS1 as a modulator of sortilin function.

KW - Adaptor Proteins, Vesicular Transport

KW - Animals

KW - CHO Cells

KW - Cell Membrane

KW - Cricetinae

KW - Cricetulus

KW - HEK293 Cells

KW - Humans

KW - Protein Binding

KW - Protein Precursors

KW - Protein Processing, Post-Translational

KW - Receptors, Cell Surface

U2 - 10.1042/BJ20130386

DO - 10.1042/BJ20130386

M3 - SCORING: Journal article

C2 - 24128306

VL - 457

SP - 277

EP - 288

JO - BIOCHEM J

JF - BIOCHEM J

SN - 0264-6021

IS - 2

ER -