Differential glycosylation regulates processing of lipoprotein receptors by gamma-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 gamma-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 splicing of an exon encoding several O-linked sugar attachment sites. These findings suggest a role for differential and tissue-specific glycosylation as a physiological switch that modulates the diverse biological functions of these receptors in a cell-type specific manner.
May
Petra
P
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA. Petra.May@UTSouthwestern.edu
Bock
Hans H
HH
Nimpf
Johannes
J
Herz
Joachim
J
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000502:physiology*; D006031:Glycosylation; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009928:Organ Specificity; D051381:Rats
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse