PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide.
ABSTRACT Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low density lipoprotein receptor (LDLR) and induces its internalization and degradation. PCSK9 binding to LDLR is mediated through the LDLR epidermal growth factor-like repeat A (EGF-A) domain. We show for the first time that an EGF-A peptide inhibits PCSK9-mediated degradation of LDLR in HepG2 cells. In addition to LDLR, we show that PCSK9 also binds directly to ApoER2 and mouse VLDLR. Importantly, binding of PCSK9 to either LDLR or mouse VLDLR was effectively inhibited by EGF-A while binding to ApoER2 was less affected. In contrast, LDL receptor-associated protein (RAP), which interacts with LDL receptor repeat type A (LA) domains, inhibited PCSK9 binding to ApoER2 with greater efficacy than either LDLR or mVLDLR. These data demonstrate that while PCSK9 binds several receptors via its EGF-A binding domain, additional contacts with other receptor domains are also involved.
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ABSTRACT: Disrupting the binding interaction between proprotein convertase (PCSK9) and the epidermal growth factor-like domain A (EGF-A domain) in the low-density lipoprotein receptor (LDL-R) is a promising strategy to promote LDL-R recycling and thereby lower circulating cholesterol levels. In this study, truncated 26 amino acid EGF-A analogs were designed and synthesized, and their structures were analyzed in solution and in complex with PCSK9. The most potent peptide had an increased binding affinity for PCSK9 (KD = 0.6 μM) compared with wild-type EGF-A (KD = 1.2 μM), and the ability to increase LDL-R recycling in the presence of PCSK9 in a cell-based assay.Chemistry & biology 01/2014; · 6.52 Impact Factor
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ABSTRACT: Statins are the first-line therapy in LDL-Cholesterol (LDL-C) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease. Yet, a significant proportion of patients remain at high risk. Recently, a number of new therapies have been developed to further lower LDL-C. These agents may provide clinical benefit on top of statin therapy in patients with high residual risk, severe hypercholesterolemia or as an alternative for patients who are intolerant to statins. We review four novel approaches based on the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein-B100 (apoB), Cholesteryl ester transport protein (CETP) and microsomal triglyceride transfer protein (MTP). ApoB and MTP inhibitors (Mipomersen and Lomitapide) are indicated only for homozygous familial hypercholesterolemia patients. The results of ongoing trials with CETP and PCSK9 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease.Current Atherosclerosis Reports 06/2014; 16(6):414. · 2.92 Impact Factor
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ABSTRACT: Proprotein convertase subtilisin/kexin 9 (PCSK9) is part of the proteinase K subfamily of subtilases and plays a key role in lipid metabolism. It increases degradation of the low-density lipoprotein receptor (LDL-R), modulates cholesterol metabolism and transport, and contributes to the production of apolipoprotein B (apoB) in intestinal cells. Exogenous PCSK9 modifies the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acyl coenzyme A:cholesterol acyltransferase and enhances secretion of chylomicrons by modulating production of lipids and apoB-48. Statins increase PCSK9 messenger RNA expression and attenuate the capacity to increase LDL-R levels. Therefore, the inhibition of PCSK9 in combination with statins provides a promising approach for lowering low-density lipoprotein cholesterol (LDL-C) concentrations. This review will address new therapeutic strategies targeting PCSK9, including monoclonal antibodies, antisense oligonucleotides, small interfering RNAs, and other small molecule inhibitors. Further studies are still needed to determine the efficacy and safety of the PCSK9 inhibitors not only to decrease LDL-C but also to investigate the potential underlying mechanisms involved and to test whether these compounds actually reduce cardiovascular end points and mortality.Journal of Cardiovascular Pharmacology and Therapeutics 06/2014; · 3.07 Impact Factor