| 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 substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that this compound was binding in an unprecedented allosteric pocket located between the catalytic and C-terminal domain. Optimization of this initial hit, using two distinct strategies, led to compounds with high binding affinity to PCSK9. Direct target engagement was demonstrated in the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.
From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9.,Petrilli WL, Adam GC, Erdmann RS, Abeywickrema P, Agnani V, Ai X, Baysarowich J, Byrne N, Caldwell JP, Chang W, DiNunzio E, Feng Z, Ford R, Ha S, Huang Y, Hubbard B, Johnston JM, Kavana M, Lisnock JM, Liang R, Lu J, Lu Z, Meng J, Orth P, Palyha O, Parthasarathy G, Salowe SP, Sharma S, Shipman J, Soisson SM, Strack AM, Youm H, Zhao K, Zink DL, Zokian H, Addona GH, Akinsanya K, Tata JR, Xiong Y, Imbriglio JE Cell Chem Biol. 2019 Oct 22. pii: S2451-9456(19)30322-8. doi:, 10.1016/j.chembiol.2019.10.002. PMID:31653597[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Petrilli WL, Adam GC, Erdmann RS, Abeywickrema P, Agnani V, Ai X, Baysarowich J, Byrne N, Caldwell JP, Chang W, DiNunzio E, Feng Z, Ford R, Ha S, Huang Y, Hubbard B, Johnston JM, Kavana M, Lisnock JM, Liang R, Lu J, Lu Z, Meng J, Orth P, Palyha O, Parthasarathy G, Salowe SP, Sharma S, Shipman J, Soisson SM, Strack AM, Youm H, Zhao K, Zink DL, Zokian H, Addona GH, Akinsanya K, Tata JR, Xiong Y, Imbriglio JE. From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9. Cell Chem Biol. 2019 Oct 22. pii: S2451-9456(19)30322-8. doi:, 10.1016/j.chembiol.2019.10.002. PMID:31653597 doi:http://dx.doi.org/10.1016/j.chembiol.2019.10.002
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