title: Disrupted recycling of the low density lipoprotein receptor by PCSK9 is not mediated by residues of the cytoplasmic domain.
abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) post-translationally regulates the number of cell-surface low density lipoprotein receptors (LDLR). This is accomplished by the ability of PCSK9 to mediate degradation of the LDLR. The underlying mechanism involves binding of secreted PCSK9 to the epidermal growth factor-like repeat A of the extracellular domain of the LDLR at the cell surface, followed by lysosomal degradation of the internalized LDLR:PCSK9 complex. However, the mechanism by which the normal recycling of the LDLR is disrupted by PCSK9, remains to be determined. In this study we have investigated the role of the cytoplasmic domain of the LDLR for this process. This has been done by studying the ability of a mutant LDLR (K811X-LDLR) which lacks the cytoplasmic domain, to be degraded by PCSK9. We show that this mutant receptor is degraded by PCSK9. Thus, the machinery which directs the LDLR:PCSK9 complex to the lysosomes for degradation, does not interact with the cytoplasmic domain of the LDLR.
authors.affiliation: Medical Genetics Laboratory, Department of Medical Genetics, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Thea Bismo
authors.initials: TB
authors.lastname: Strøm
authors.forename: Øystein L
authors.initials: ØL
authors.lastname: Holla
authors.forename: Kristian
authors.initials: K
authors.lastname: Tveten
authors.forename: Jamie
authors.initials: J
authors.lastname: Cameron
authors.forename: Knut Erik
authors.initials: KE
authors.lastname: Berge
authors.forename: Trond P
authors.initials: TP
authors.lastname: Leren
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D011973:Receptors, LDL; D012697:Serine Endopeptidases