| Structural highlights
Disease
[PCSK9_HUMAN] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:603776]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.[1]
Function
[PCSK9_HUMAN] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.[2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with autosomal dominant hypercholesterolemia, a state of elevated levels of LDL (low-density lipoprotein) cholesterol. Autosomal dominant hypercholesterolemia can result in severe implications such as stroke and coronary heart disease. The inhibition of PCSK9 function by therapeutic antibodies that block interaction of PCSK9 with the epidermal growth factor-like repeat A domain of LDL receptor (LDLR) was shown to successfully lower LDL cholesterol levels in clinical studies. Here we present data on the identification, structural and biophysical characterization and in vitro and in vivo pharmacology of a PCSK9 antibody (mAb1). The X-ray structure shows that mAb1 binds the module 1 of the C-terminal domain (CTD) of PCSK9. It blocks access to an area bearing several naturally occurring gain-of-function and loss-of-function mutations. Although the antibody does not inhibit binding of PCSK9 to epidermal growth factor-like repeat A, it partially reverses PCSK9-induced reduction of the LDLR and LDL cholesterol uptake in a cellular assay. mAb1 is also effective in lowering serum levels of LDL cholesterol in cynomolgus monkeys in vivo. Complete loss of PCSK9 is associated with insufficient liver regeneration and increased risk of hepatitis C infections. Blocking of the CTD is sufficient to partially inhibit PCSK9 function. Antibodies binding the CTD of PCSK9 may thus be advantageous in patients that do not tolerate complete inhibition of PCSK9.
An Antibody against the C-Terminal Domain of PCSK9 Lowers LDL Cholesterol Levels InVivo.,Schiele F, Park J, Redemann N, Luippold G, Nar H J Mol Biol. 2013 Nov 16. pii: S0022-2836(13)00722-5. doi:, 10.1016/j.jmb.2013.11.011. PMID:24252255[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003 Jun;34(2):154-6. PMID:12730697 doi:10.1038/ng1161
- ↑ Nassoury N, Blasiole DA, Tebon Oler A, Benjannet S, Hamelin J, Poupon V, McPherson PS, Attie AD, Prat A, Seidah NG. The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic. 2007 Jun;8(6):718-32. Epub 2007 Apr 25. PMID:17461796 doi:10.1111/j.1600-0854.2007.00562.x
- ↑ Fan D, Yancey PG, Qiu S, Ding L, Weeber EJ, Linton MF, Fazio S. Self-association of human PCSK9 correlates with its LDLR-degrading activity. Biochemistry. 2008 Feb 12;47(6):1631-9. doi: 10.1021/bi7016359. Epub 2008 Jan 16. PMID:18197702 doi:10.1021/bi7016359
- ↑ Jonas MC, Costantini C, Puglielli L. PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep. 2008 Sep;9(9):916-22. doi: 10.1038/embor.2008.132. Epub 2008 Jul 25. PMID:18660751 doi:10.1038/embor.2008.132
- ↑ Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, Nassoury N, Mayer H, Nimpf J, Prat A, Seidah NG. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J Biol Chem. 2008 Jan 25;283(4):2363-72. Epub 2007 Nov 26. PMID:18039658 doi:10.1074/jbc.M708098200
- ↑ Chen Y, Wang H, Yu L, Yu X, Qian YW, Cao G, Wang J. Role of ubiquitination in PCSK9-mediated low-density lipoprotein receptor degradation. Biochem Biophys Res Commun. 2011 Nov 25;415(3):515-8. doi:, 10.1016/j.bbrc.2011.10.110. Epub 2011 Nov 2. PMID:22074827 doi:10.1016/j.bbrc.2011.10.110
- ↑ Sun H, Samarghandi A, Zhang N, Yao Z, Xiong M, Teng BB. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. Arterioscler Thromb Vasc Biol. 2012 Jul;32(7):1585-95. doi:, 10.1161/ATVBAHA.112.250043. Epub 2012 May 10. PMID:22580899 doi:10.1161/ATVBAHA.112.250043
- ↑ Sharotri V, Collier DM, Olson DR, Zhou R, Snyder PM. Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). J Biol Chem. 2012 Jun 1;287(23):19266-74. doi: 10.1074/jbc.M112.363382. Epub 2012, Apr 9. PMID:22493497 doi:10.1074/jbc.M112.363382
- ↑ Schiele F, Park J, Redemann N, Luippold G, Nar H. An Antibody against the C-Terminal Domain of PCSK9 Lowers LDL Cholesterol Levels InVivo. J Mol Biol. 2013 Nov 16. pii: S0022-2836(13)00722-5. doi:, 10.1016/j.jmb.2013.11.011. PMID:24252255 doi:http://dx.doi.org/10.1016/j.jmb.2013.11.011
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