title: Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors.
abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) at the cell surface and disrupts the normal recycling of the LDLR. In this study, we investigated the role of the C-terminal domain for the activity of PCSK9. Experiments in which conserved residues and histidines on the surface of the C-terminal domain were mutated indicated that no specific residues of the C-terminal domain, apart from those responsible for maintaining the overall structure, are required for the activity of PCSK9. Rather, the net charge of the C-terminal domain is important. The more positively charged the C-terminal domain, the higher the activity toward the LDLR. Moreover, replacement of the C-terminal domain with an unrelated protein of comparable size led to significant activity of the chimeric protein. We conclude that the role of the evolutionary, poorly conserved C-terminal domain for the activity of PCSK9 reflects its overall positive charge and size and not the presence of specific residues involved in protein-protein interactions.
authors.affiliation: Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
authors.forename: Øystein L
authors.initials: ØL
authors.lastname: Holla
authors.forename: Jamie
authors.initials: J
authors.lastname: Cameron
authors.forename: Kristian
authors.initials: K
authors.lastname: Tveten
authors.forename: Thea Bismo
authors.initials: TB
authors.lastname: Strøm
authors.forename: Knut Erik
authors.initials: KE
authors.lastname: Berge
authors.forename: Jon K
authors.initials: JK
authors.lastname: Laerdahl
authors.forename: Trond P
authors.initials: TP
authors.lastname: Leren
mesh_terms: D000409:Alanine / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism*; D056945:Hep G2 Cells; D006639:Histidine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011485:Protein Binding; D011973:Receptors, LDL / Q000737:chemistry / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D011973:Receptors, LDL; D006639:Histidine; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000409:Alanine