Degradation of LDLR protein mediated by ‘gain of function’ PCSK9 mutants in normal and ARH cells

Abifadel, 2003, Mutations in PCSK9 cause autosomal dominant hypercholesterolemia, Nat Genet, 34, 154, 10.1038/ng1161 Cohen, 2005, Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9, Nat Genet, 37, 161, 10.1038/ng1509 Seidah, 2003, The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation, Proc Natl Acad Sci U S A, 100, 928, 10.1073/pnas.0335507100 Maxwell, 2003, Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice, J Lipid Res, 44, 2109, 10.1194/jlr.M300203-JLR200 Horton, 2003, Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes, Proc Natl Acad Sci U S A, 100, 12027, 10.1073/pnas.1534923100 Park, 2004, Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver, J Biol Chem, 279, 50630, 10.1074/jbc.M410077200 Maxwell, 2005, Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment, Proc Natl Acad Sci U S A, 102, 2069, 10.1073/pnas.0409736102 Lagace, 2006, Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice, J Clin Invest, 116, 2995, 10.1172/JCI29383 Zhang, 2007, Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation, J Biol Chem, 282, 18602, 10.1074/jbc.M702027200 Kwon, 2008, Molecular basis for LDL receptor recognition by PCSK9, Proc Natl Acad Sci U S A, 105, 1820, 10.1073/pnas.0712064105 Rashid, 2005, Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9, Proc Natl Acad Sci U S A, 102, 5374, 10.1073/pnas.0501652102 Cohen, 2006, Sequence variations in PCSK9, low LDL, and protection against coronary heart disease, N Engl J Med, 354, 1264, 10.1056/NEJMoa054013 Fasano, 2007, A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol, Arterioscler Thromb Vasc Biol, 27, 677, 10.1161/01.ATV.0000255311.26383.2f Naoumova, 2005, Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response, Arterioscler Thromb Vasc Biol, 25, 2654, 10.1161/01.ATV.0000190668.94752.ab Cunningham, 2007, Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia, Nat Struct Mol Biol, 14, 413, 10.1038/nsmb1235 Cameron, 2006, Effect of mutations in the PCSK9 gene on the cell surface LDL receptors, Hum Mol Genet, 15, 1551, 10.1093/hmg/ddl077 Homer, 2008, Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa, Atherosclerosis, 196, 659, 10.1016/j.atherosclerosis.2007.07.022 Pandit, 2008, Functional analysis of sites within PCSK9 responsible for hypercholesterolemia, J Lipid Res, 49, 1333, 10.1194/jlr.M800049-JLR200 Bourbon, 2008, Familial hypercholesterolaemia in Portugal, Atherosclerosis, 196, 633, 10.1016/j.atherosclerosis.2007.07.019 Pisciotta, 2006, Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia, Atherosclerosis, 186, 433, 10.1016/j.atherosclerosis.2005.08.015 Eden, 2002, Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1, J Clin Invest, 110, 1695, 10.1172/JCI0216445 Norman, 1999, Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia, J Clin Invest, 104, 619, 10.1172/JCI6677 Sun, 2005, Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia, Hum Mol Genet, 14, 1161, 10.1093/hmg/ddi128 Horton, 2007, Molecular biology of PCSK9: its role in LDL metabolism, Trends Biochem Sci, 32, 71, 10.1016/j.tibs.2006.12.008 Hampton, 2007, The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain, Proc Natl Acad Sci U S A, 104, 14604, 10.1073/pnas.0703402104 Michaely, 2007, Identification of a VLDL-induced, FDNPVY-independent internalization mechanism for the LDLR, EMBO J, 26, 3273, 10.1038/sj.emboj.7601769 Holla, 2007, Degradation of the LDL receptors by PCSK9 is not mediated by a secreted protein acted upon by PCSK9 extracellularly, BMC Cell Biol, 8, 9, 10.1186/1471-2121-8-9 Grefhorst, 2008, Plasma PCSK9 preferentially reduces liver LDL receptors in mice, J Lipid Res, 49, 1303, 10.1194/jlr.M800027-JLR200