The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein.
Sortilin belongs to a growing family of multiligand type-1 receptors with homology to the yeast receptor Vps10p. Based on structural features and sortilin's intracellular predominance, we have proposed it to be a sorting receptor for ligands in the synthetic pathway as well as on the cell membrane. To test this hypothesis we examine here the cellular trafficking of chimeric receptors containing constructs of the sortilin tail. We report that sorting signals conforming to YXX and dileucine motifs mediate rapid endocytosis of sortilin chimeras, which subsequently travel to the trans-Golgi network, showing little or no recycling. Furthermore, we found that cation-independent mannose 6-phosphate receptor (MPR300)-sortilin chimeras, expressed in mannose 6-phosphate receptor knockout cells, were almost as efficient as MPR300 itself for transport of newly synthesized beta-hexosaminidase and beta-glucuronidase to lysosomes, and established that the sortilin tail contains potent signals for Golgi-endosome sorting. Finally, we provide evidence suggesting that sortilin is the first example of a mammalian receptor targeted by the recently described GGA family of cytosolic sorting proteins, which condition the Vps10p-mediated sorting of yeast carboxypeptidase Y.
Nielsen
M S
MS
Department of Medical Biochemistry and Department of Cell Biology, University of Aarhus, 8000 Aarhus C, Denmark. mn@biokemi.au.dk
Madsen
P
P
Christensen
E I
EI
Nykjaer
A
A
Gliemann
J
J
Kasper
D
D
Pohlmann
R
R
Petersen
C M
CM
D033942:Adaptor Proteins, Vesicular Transport; D020816:Amino Acid Motifs / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics; D015870:Gene Expression; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D014162:Transfection; D020798:Two-Hybrid System Techniques; D033921:Vesicular Transport Proteins; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D005656:Fungal Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D033921:Vesicular Transport Proteins; D000099183:Sortilin; C405944:GGA2 protein, human; C087335:PEP1 protein, S cerevisiae