title: Human sorCS1 binds sortilin and hampers its cellular functions.
abstract: 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.
authors.affiliation: *The MIND center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Jakob Vejby
authors.initials: JV
authors.lastname: Larsen
authors.affiliation: †Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Hermey
authors.affiliation: ‡Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Esben Skipper
authors.initials: ES
authors.lastname: Sørensen
authors.affiliation: §Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Thaneas
authors.initials: T
authors.lastname: Prabakaran
authors.affiliation: §Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Erik Ilsø
authors.initials: EI
authors.lastname: Christensen
authors.affiliation: *The MIND center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Gliemann
authors.affiliation: *The MIND center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Peder
authors.initials: P
authors.lastname: Madsen
authors.affiliation: *The MIND center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Claus Munck
authors.initials: CM
authors.lastname: Petersen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D011485:Protein Binding / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D011498:Protein Precursors; D011956:Receptors, Cell Surface; D000099183:Sortilin; C472780:SORCS1 protein, human