Regulatory effects of peptides from the pro and catalytic domains of proprotein convertase subtilisin/kexin 9 (PCSK9) on low-density lipoprotein receptor (LDL-R)

Current Medicinal Chemistry

Volumn 17, Issue 20, 2010, Pages 2168-2182

  Palmer Smith, H ^a   Basak, A ^a  

^a OTTAWA HOSPITAL RESEARCH INSTITUTE   (Canada)

Author keywords

Cholesterol regulation; Low density lipoprotein receptor; PCSK9 inhibitors; Proprotein convertase subtilisin kexin9 (PCSK9)

Indexed keywords

ASPARAGINE; ENZYME INHIBITOR; LOW DENSITY LIPOPROTEIN RECEPTOR; PROPROTEIN CONVERTASE SUBTILISIN/KEXIN 9; SERINE; SUBTILISIN; TRANSFERRIN RECEPTOR; UNCLASSIFIED DRUG; PCSK9 PROTEIN, HUMAN; PEPTIDE; RECOMBINANT PROTEIN; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR;

AMINO ACID SEQUENCE; ARTICLE; CATALYSIS; CONTROLLED STUDY; GENE DELETION; GENE MUTATION; HUMAN; HUMAN CELL; IMMUNOBLOTTING; NUCLEOTIDE SEQUENCE; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN MODIFICATION; PROTEIN STRUCTURE; WESTERN BLOTTING; CHEMISTRY; CIRCULAR DICHROISM; ENZYME ACTIVE SITE; GENETICS; METABOLISM; MOLECULAR GENETICS; PROTEIN SECONDARY STRUCTURE; PROTEIN TERTIARY STRUCTURE; SYNTHESIS; TUMOR CELL LINE;

AMINO ACID SEQUENCE; CATALYTIC DOMAIN; CELL LINE, TUMOR; CIRCULAR DICHROISM; HUMANS; MOLECULAR SEQUENCE DATA; PEPTIDES; PROPROTEIN CONVERTASES; PROTEIN STRUCTURE, SECONDARY; PROTEIN STRUCTURE, TERTIARY; RECEPTORS, LDL; RECOMBINANT PROTEINS; SERINE ENDOPEPTIDASES; SERINE PROTEINASE INHIBITORS;

EID: 77955652065     PISSN: 09298673     EISSN: None     Source Type: Journal    
DOI: 10.2174/092986710791299948     Document Type: Article

References (38)

1. Seidah, N.G.; Benjannet, S.; Wickham, L.; Marcinkiewicz, J.; Jasmin, S. B.; Stifani, S.; Basak, A.; Prat, A.; Chretien, M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA, 2003, 100, 928-933.
2. Qian, Y.W.; Schmidt, R.J.; Zhang, Y.; Chu, S, Lin, A.; Wang, H.; Wang, X.; Beyer, T.P.; Bensch, W.R.; Li, W.; Ehsani, M.E.; Lu, D.; Konrad, R.J.; Eacho, P.I.; Moller, D.E.; Karathanasis, S.K.; Cao, G. Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J. Lipid Res., 2007, 48, 1488-1498.
3. Fan, D.; Yancey, P.G.; Qiu, S.; Ding, L.; Weeber, E.J.; Linton, M.F.; Fazio, S. Self-association of human PCSK9 correlates with its LDLR-degrading activity. Biochemistry, 2008, 47, 1631-1639.
4. Abifadel, M.; Rabes, J.P.; Boileau, C.; Varret, M. After the LDL receptor and apolipoprotein B, autosomal dominant hypercholesterolemia reveals its third protagonist: PCSK9. Ann. Endocrinol. (Paris), 2007, 68, 138-146.
5. Fisher, T.S.; Lo Surdo, P.; Pandit, S.; Mattu, M.; Santoro, J.C.; Wisniewski, D.; Cummings, R.T.; Calzetta, A.; Cubbon, R.M.; Fischer, P.A.; Tarachandani, A.; De Francesco, R.; Wright, S.D.; Sparrow, C.P.; Carfi, A.; Sitlani, A. Effects of pH and low density lipoprotein (LDL) on PCSK9-dependent LDL receptor regulation. J. Biol. Chem., 2007, 282, 20502-20512.
6. Benjannet, S.; Rhainds, D.; Essalmani, R.; Mayne, J.; Wickham, L.; Jin, W.; Asselin, M.C.; Hamelin, J.; Varret, M.; Allard, D.; Trillard, M.; Abifadel, M.; Tebon, A.; Attie, A.D.; Rader, D. J.; Boileau, C.; Brissette, L.; Chrétien, M.; Prat, A.; Seidah, N.G. NARC-1/PCSK9 and its natural mutants: Zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J. Biol. Chem., 2004, 279, 48865-48875.
7. Salvas, A.; Benjannet, S.; Reudelhuber, T.L.; Chrétien. M.; Seidah, N.G. Evidence for proprotein convertase activity in the endoplasmic reticulum/early Golgi. FEBS Lett, 2005, 579(25), 5621-5625.
8. Kourimate, S.; Chetiveaux, M.; Jarnoux, A.L.; Lalanne, F.; Costet, P. Cellular and secreted pro-protein convertase subtilisin/kexin type 9 catalytic activity in hepatocytes. Atherosclerosis, 2009, 206, 134-140
9. Costet, P.; Krempf, M.; Cariou, B. PCSK9 and LDL cholesterol: Unravelling the target to design the bullet. Trends Biochem., Sci., 2008, 33, 426-434.
10. Abifadel, M.; Bernier, L.; Dubuc, G.; Nuel, G.; Rabès, J. P.; Bonneau, J.; Marques, A.; Marduel, M.; Devillers, M.; Munnich, A.; Erlich, D.; Varret, M.; Roy, M.; Davignon, J.; Boileau, C.A PCSK9 variant and familial combined hyperlipidemia. J. Med. Genet., 2008, 45, 780-786.
11. Pandit, S.; Wisniewski, D.; Santoro, J.C.; Santoro, J.C.; Ha, S.; Ramakrishnan, V.; Cubbon, R.M.; Cummings, R.T.; Wright, S.D.; Sparrow, C.P.; Sitlani, A.; Fisher, T. S. Functional analysis of sites within PCSK9 responsible for hypercholesterolemia. J. Lipid Res., 2008, 49, 1333-1343.
12. Schmidt, R.J.; Beyer, T.P.; Bensch, W.R.; Qian, Y.W.; Lin, A.; Kowala, M.; Alborn, W.E.; Konrad, R.J.; Cao, G. Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo. Biochem. Biophys. Res. Commun., 2008, 370, 634-640.
13. Zhang, D.W.; Lagace, T.A.; Garuti, R.; Zhao, Z.; McDonald, M.; Horton, J.D.; Cohen, J.C.; Hobbs, H.H. 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., 2007, 282, 18602-18612.
14. Poirier, S.; Mayer, G.; Benjannet, S.; Bergeron, E.; Marcinkiewicz, J.; Nassoury, N.; Mayer, H.; Nimpf, J.; Prat, A.; Seidah, N.G. 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, 283, 2363-2372.
15. Dubuc, G.; Chamberland, A.; Wassef, H.; Davignon, J.; Seidah, N.G.; Bernier, L.; Prat, A. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase- 1 implicated in familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol., 2004, 24, 1454-1459.
16. Grozdanov, P.N.; Petkov, P.M.; Karagyozov, L.K.; Dabeva, M.D. Expression and localization of PCSK9 in rat hepatic cells. Biochem. Cell. Biol, 2006, 84, 80-92.
17. Zhang, D.W.; Garuti, R.; Tang, W.J.; Cohen, J.C.; Hobbs, H.H. Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor. Proc. Natl. Acad. Sci. USA, 2008, 105, 13045-13050.
18. Hampton, E.N.; Knuth, M.W.; Li, J.; Harris, J.L.; Lesley, S.A.; Spraggon, G. The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the Cterminal domain. Proc. Natl. Acad. Sci. USA, 2007, 104(37), 14604-14609.
19. Kwon, H.J.; Lagace, T.A.; McNutt, M.C.; Horton, J.D.; Deisenhofer, J. Molecular basis for LDL receptor recognition by PCSK9. Proc. Natl. Acad. Sci. USA, 2008 105, 1820-1825.
20. Bottomley, M.J.; Cirillo, A.; Orsatti, L.; Ruggeri, L.; Fisher, T.S.; Santoro, J.C.; Cummings, R.T.; Cubbon, R.M., Lo Surdo, P.; Calzetta, A.; Noto, A.; Baysarowich, J.; Mattu, M.; Talamo, F.; De Francesco, R.; Sparrow, C.P.; Sitlani, A.; Carfí, A. Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants. J. Biol. Chem., 2009, 284, 1313-1323.
21. Cunningham, D.; Danley, D.E.; Geoghegan, K.F.; Griffor, M.C.; Hawkins, J.L.; Subashi, T.A.; Varghese, A.H.; Ammirati, M.J.; Culp, J.S.; Hoth, L.R.; Mansour, M.N.; McGrath, K.M.; Seddon, A.P.; Shenolikar, S.; Stutzman-Engwall, K. J.; Warren, L. C.; Xia, D.; Qiu, X. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat. Struct. Mol. Biol., 2007, 14, 413-419.
22. Dewpura, T.; Raymond, A.; Hamelin, J.; Seidah, N.G.; Mbikay, M.; Chrétien, M.; Mayne, J. PCSK9 is phosphorylated by a golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans. FEBS J., 2008, 275, 3480-3493
23. Seidah, N.G.; Mayer, G.; Zaid, A.; Rousselet, E.; Nassoury, N.; Poirier, S.; Essalmani, R.; Prat, A. The activation and physiological functions of the proprotein convertases. Int. J. Biochem. Cell Biol., 2008, 40, 1111-1125.
24. Basak, A.; Lotfipour, F. Modulating furin activity with designed mini-PDX peptides: Synthesis and in vitro kinetic evaluation. FEBS Lett, 2005, 579, 4813-4821.
25. Day, R.; Schafer, M.K.; Cullinan, W.E.; Watson, S.J.; Chretien, M.; Seidah, N.G. Region specific expression of furin mRNA in the rat brain. Neurosci. Lett., 1993, 149, 27-30.
26. Komiyama, T.; Coppola, J.M.; Larsen, M.J.; van Dort, M.E.; Ross, B.D.; Day, R.; Rehemtulla, A.; Fuller, R.S. Inhibition of furin/proprotein convertase-catalyzed surface and intracellular processing by small molecules. J. Biol. Chem., 2009, 284, 15729-15738.
27. Whitmore, L.; Wallace, B.A. Protein secondary structure analyses from circular dichroism spectroscopy: methods and reference databases. Biopolymers, 2008, 89, 392-400.
28. Abifadel, M.; Rabes, J.P.; Devillers, M.; Munnich, A.; Erlich, D.; Junien, C.; Varret, M.; Boileau, C. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum. Mutat., 2009, 30, 520-529.
29. Piper, D.E.; Jackson, S.; Liu, Q.; Romanow, W.G.; Shetterly, S.; Thibault, S.T.; Shan, B.; Walker, N.P. The crystal structure of PCSK9: A regulator of plasma LDL- cholesterol. Structure, 2007, 15, 545-552.
30. Steinberg, D.; Witztum, J.L. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels. Proc. Natl. Acad. Sci. USA, 2009, 106, 9546-9547.
31. Lopez, D. Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia. Drug News Perspect., 2008, 21, 323-330.
32. Zhou, Q.; Liao, J.K. Statins and cardiovascular diseases: from cholesterol lowering to pleiotropy. Curr. Pharm. Des., 2009, 15, 467-478.
33. Remick, J.; Weintraub, H.; Setton, R. Offenbacher, J.; Fisher, E.; Schwartzbard, A. Fibrate therapy: an update. Cardiol. Rev., 2008, 16, 129-141.
34. Chan, J.C.; Piper, D.E.; Cao, Q.; Liu, D.; King, C.; Wang, W.; Tang, J.; Liu, Q.; Higbee, J.; Xia, Z.; Di, Y.; Shetterly, S.; Arimura, Z.; Salomonis, H.; Romanow, W.G.; Thibault, S.T.; Zhang, R.; Cao, P.; Yang, X.P.; Yu, T.; Lu, M.; Retter, M.W.; Kwon, G.; Henne, K.; Pan, O.; Tsai, M.M.; Fuchslocher, B.; Yang, E.; Zhou, L.; Lee, K.J.; Daris, M.; Sheng, J.; Wang, Y.; Shen, W.D.; Yeh, W.C.; Emery, M.; Walker, N.P.; Shan, B.; Schwarz, M.; Jackson, S.M. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc. Natl. Acad. Sci. USA, 2009, 106(24), 9820-9825.
35. Graham, M.J.; Lemonidis, K.M.; Whipple, C.P.; Subramaniam, A.; Monia, B.P.; Crooke, S.T.; Crooke, R.M. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res., 2007, 48(4), 763-767.
36. Scamuffa, N.; Calvo, F.; Chrétien, M.; Seidah, N.G.; Khatib, A.M. Proprotein convertases: lessons from knockouts. FASEB J, 2006, 20, 1954-1963.
37. Chrétien, M.; Seidah, N.G.; Basak, A.; Mbikay, M. Proprotein convertases as therapeutic targets. Expert Opin. Ther. Targets, 2008, 12, 1289-1300.
38. Shan, L.; Pang, L.; Zhang, R.; Murgolo, N.J.; Lan, H.; Hedrick, J.A. PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide. Biochem. Biophys. Res. Commun., 2008, 375, 69-73.