title: PCSK9-mediated degradation of the LDL receptor generates a 17 kDa C-terminal LDL receptor fragment.
abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the LDL receptor (LDLR) at the cell surface and reroutes the internalized LDLR to intracellular degradation. In this study, we have shown that PCSK9-mediated degradation of the full-length 160 kDa LDLR generates a 17 kDa C-terminal LDLR fragment. This fragment was not generated from mutant LDLRs resistant to PCSK9-mediated degradation or when degradation was prevented by chemicals such as ammonium chloride or the cysteine cathepsin inhibitor E64d. The observation that the 17 kDa fragment was only detected when the cells were cultured in the presence of the γ-secretase inhibitor DAPT indicates that this 17 kDa fragment undergoes γ-secretase cleavage within the transmembrane domain. The failure to detect the complementary 143 kDa ectodomain fragment is likely to be due to its rapid degradation in the endosomal lumen. The 17 kDa C-terminal LDLR fragment was also generated from a Class 5 mutant LDLR undergoing intracellular degradation. Thus, one may speculate that an LDLR with bound PCSK9 and a Class 5 LDLR with bound LDL are degraded by a similar mechanism that could involve ectodomain cleavage in the endosome.
authors.affiliation: Department of Medical Genetics, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Tveten
authors.affiliation: Department of Medical Genetics, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Thea Bismo
authors.initials: TB
authors.lastname: Str M
authors.affiliation: Department of Medical Genetics, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Knut Erik
authors.initials: KE
authors.lastname: Berge
authors.affiliation: Department of Medical Genetics, Oslo University Hospital Rikshospitalet, Oslo, Norway. Electronic address: trond.leren@rikshospitalet.no.
authors.forename: Trond P
authors.initials: TP
authors.lastname: Leren
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: C573412:LDLR protein, human; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D053829:Amyloid Precursor Protein Secretases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: cathepsin; cleavage; degradation; endosome; low density lipoprotein