Human sorCS1 binds sortilin and hampers its cellular functions
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Human sorCS1 binds sortilin and hampers its cellular functions. / Larsen, Jakob Vejby; Hermey, Guido; Sørensen, Esben Skipper; Prabakaran, Thaneas; Christensen, Erik Ilsø; Gliemann, Jørgen; Madsen, Peder; Petersen, Claus Munck.
In: BIOCHEM J, Vol. 457, No. 2, 15.01.2014, p. 277-88.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -