Carbohydrate- and conformation-dependent cargo capture for ER-exit.
Some secretory proteins leave the endoplasmic reticulum (ER) by a receptor-mediated cargo capture mechanism, but the signals required for the cargo-receptor interaction are largely unknown. Here, we describe a novel targeting motif that is composed of a high-mannose type oligosaccharide intimately associated with a surface-exposed peptide beta-hairpin loop. The motif accounts for lectin ERGIC-53-assisted ER-export of the lyososomal enzyme procathepsin Z. The second oligosaccharide chain of procathepsin Z exhibits no binding activity for ERGIC-53, illustrating the selective lectin properties of ERGIC-53. Our data suggest that the conformation-based motif is only present in fully folded procathepsin Z and that its recognition by ERGIC-53 reflects a quality control mechanism that acts complementary to the primary folding machinery in the ER. A similar oligosaccharide/beta-hairpin loop structure is present in cathepsin C, another cargo of ERGIC-53, suggesting the general nature of this ER-exit signal. To our knowledge this is the first documentation of an ER-exit signal in soluble cargo in conjunction with its decoding by a transport receptor.
Appenzeller-Herzog
Christian
C
Department of Pharmacology and Neurobiology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
Nyfeler
Beat
B
Burkhard
Peter
P
Santamaria
Inigo
I
Lopez-Otin
Carlos
C
Hauri
Hans-Peter
HP
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002241:Carbohydrates / Q000737:chemistry*; D002352:Carrier Proteins / Q000737:chemistry; D020789:Cathepsin C / Q000737:chemistry; D056657:Cathepsin K; D002403:Cathepsins / Q000737:chemistry; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006023:Glycoproteins / Q000737:chemistry; D006026:Glycoside Hydrolases / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D037102:Lectins / Q000737:chemistry / Q000378:metabolism; D037241:Mannose-Binding Lectins / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D009844:Oligosaccharides / Q000737:chemistry*; D011134:Polysaccharides / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D021382:Protein Sorting Signals; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D002241:Carbohydrates; D002352:Carrier Proteins; D003432:Cross-Linking Reagents; D018076:DNA, Complementary; D006023:Glycoproteins; C084004:LMAN1 protein, human; D037102:Lectins; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D009844:Oligosaccharides; D011134:Polysaccharides; D021382:Protein Sorting Signals; D004247:DNA; D006026:Glycoside Hydrolases; D002403:Cathepsins; D020789:Cathepsin C; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse