Differential Glycosylation Regulates Processing of Lipoprotein Receptors by γ-Secretase

The low density lipoprotein (LDL) receptor-related protein 1 (LRP1) belongs to a growing number of cell surface proteins that undergo regulated proteolytic processing that culminates in the release of their intracellular domain (ICD) by the intramembranous protease γ-secretase. Here we show that LRP1 is differentially glycosylated in a tissue-specific manner and that carbohydrate addition reduces proteolytic cleavage of the extracellular domain and, concomitantly, ICD release. The apolipoprotein E (apoE) receptor-2 (apoER2), another member of the LDL receptor family with functions in cellular signal transmission, also undergoes sequential proteolytic processing, resulting in intracellular domain release into the cytoplasm. The penultimate processing step also involves cleavage of the apoER2 extracellular domain. The rate at which this cleavage step occurs is determined by the glycosylation state of the receptor, which in turn is regulated by the alternative of a and tissue-specific glycosylation a that the functions of in a The low density lipoprotein (LDL) receptor-related protein 1 (LRP1) belongs to a growing number of cell surface proteins that undergo regulated proteolytic processing that culminates in the release of their intracellular domain (ICD) by the intramembranous protease γ-secretase. Here we show that LRP1 is differentially glycosylated in a tissue-specific manner and that carbohydrate addition reduces proteolytic cleavage of the extracellular domain and, concomitantly, ICD release. The apolipoprotein E (apoE) receptor-2 (apoER2), another member of the LDL receptor family with functions in cellular signal transmission, also undergoes sequential proteolytic processing, resulting in intracellular domain release into the cytoplasm. The penultimate processing step also involves cleavage of the apoER2 extracellular domain. The rate at which this cleavage step occurs is determined by the glycosylation state of the receptor, which in turn is regulated by the alternative of a and tissue-specific glycosylation a that the functions of in a The low density lipoprotein (LDL) low density low density lipoprotein low density lipoprotein receptor-related protein low density low density lipoprotein low density lipoprotein receptor-related protein receptor family a of cell surface the of a of extracellular that and and their and with functions in in cellular signal also and of the by which LDL receptor family cellular and to the of the LDL receptor family glycosylation and the LDL receptor, the low density lipoprotein receptor and the also a and that their domain. domain domain in The to which the undergo glycosylation is in and that the domain apoER2 and is the of the carbohydrate the of glycosylation is to the of the receptor cell with of LDL of in glycosylation resulting in receptor of the domain is apoER2 and differentially in and which functions of the regulated by the of the the of of to of their surface of the also that by a of this in the release of the intracellular domain (ICD) into the by into the in the of in of by is in which the processing of proteolytic processing that is regulated by the glycosylation state of the protein is that of the which is also by carbohydrate we that the LDL receptor-related protein 1 which is in a by a of cleavage that in the release of is differentially glycosylated in a tissue-specific that this glycosylation of LRP1 to the rate at which LRP1 is and LRP1 cleavage in the glycosylation cell we show that the glycosylation state of this protein the rate of the extracellular cleavage step that in the of the LRP1 is the protein is which in turn in the release of the LRP1 we that the apoER2 also in in cell and that the of domain the rate at which the ICD of apoER2 is and The in of and the the apoER2 domain by of the of the apoER2 and with domain a of the and 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the in and with which carbohydrate in of LRP1 with with with the of LRP1 in LRP1 is differentially in and is of a of in the to the LDL receptor, which is is glycosylation of LRP1 in of the the LDL receptor, and a and which the domain domain carbohydrate domain is by a in of the and that the domain and with we the of by the that the the domain also in the of apoER2 the receptor that the which in with of LRP1 by in of this tissue-specific glycosylation of LDL receptor family is that glycosylation the of of the which undergo regulated processing, of the family and the of proteolytic cleavage by their glycosylation state we that protein and also undergo proteolytic processing, resulting in the release of this processing by the glycosylation state of LRP1 we a cell which the to and in cell the to of their in LDL protein is is and state of the LDL receptor in LRP1 is of in proteolytic processing of and and the in the of and with of of cell and by with the of and and with 1 of 1 of of and of 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rate at which LRP1 is and LRP1 cleavage in the glycosylation cell we show that the glycosylation state of this protein the rate of the extracellular cleavage step that in the of the LRP1 is the protein is which in turn in the release of the LRP1 we that the apoER2 also in in cell and that the of domain the rate at which the ICD of apoER2 is and The in of and the the apoER2 domain by of the of the apoER2 and with domain a of the and the with The into the and by domain and 1 and and of the the The and with and and to 1 and The resulting by the in and by and of the and the which and the in of the and of and cell cell and the cell in at in in and low and and by and with the of the with a of and a of in and at to of and in with of and apoER2 and and by in of to in the of and with into 1 of and at at in 1 and a at at the at the in 1 of and and with and and in 1 and protease of at and at The to at at The of this step in protease and at at The protein of the determined of proteins the with and 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