Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation

Journal of Biological Chemistry

Volumn 288, Issue 12, 2013, Pages 8279-8288

  Kosenko, Tanja ^a   Golder, Mia ^a   Leblond, Geoffrey ^a   Weng, Willy ^a   Lagace, Thomas A ^a  

^a UNIVERSITY OF OTTAWA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOSOMAL DOMINANTS; DENSITY GRADIENT CENTRIFUGATION; EPIDERMAL GROWTH; HIGH MOLECULAR WEIGHT; HYPERCHOLESTEROLEMIA; LOW DENSITY LIPOPROTEIN RECEPTORS; LOW DENSITY LIPOPROTEINS; SECRETED PROTEIN;

AMINO ACIDS; CELL MEMBRANES; CENTRIFUGATION; PLASMA (HUMAN);

SIZE EXCLUSION CHROMATOGRAPHY;

KEXIN; KEXIN 9; LOW DENSITY LIPOPROTEIN; LOW DENSITY LIPOPROTEIN RECEPTOR; RECOMBINANT PROTEIN; SUBTILISIN; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; AMINO TERMINAL SEQUENCE; ARTICLE; BINDING COMPETITION; CELL SURFACE; CHEMICAL LABELING; CONTROLLED STUDY; DENSITY GRADIENT CENTRIFUGATION; DRUG PROTEIN BINDING; ENZYME INHIBITION; ENZYME REGULATION; FEMALE; GAIN OF FUNCTION MUTATION; GEL PERMEATION CHROMATOGRAPHY; GENE IDENTIFICATION; GENETIC ASSOCIATION; HUMAN; HUMAN CELL; HYPERCHOLESTEROLEMIA; IN VITRO STUDY; LIVER CELL; MALE; MOLECULAR WEIGHT; PARTICLE SIZE; PCSK9 GENE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN BLOOD LEVEL; PROTEIN DEGRADATION; PROTEIN DETERMINATION; PROTEIN DOMAIN; PROTEIN ISOLATION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING;

BINDING, COMPETITIVE; CELL LINE, TUMOR; HEK293 CELLS; HUMANS; LIPOPROTEINS, HDL; LIPOPROTEINS, LDL; LIPOPROTEINS, VLDL; PROPROTEIN CONVERTASES; PROTEIN BINDING; PROTEIN INTERACTION DOMAINS AND MOTIFS; PROTEOLYSIS; RECEPTORS, LDL; SERINE ENDOPEPTIDASES;

EID: 84875460859     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M112.421370     Document Type: Article

References (52)

1. Goldstein, J. L., and Brown, M. S. (2009) The LDL receptor. Arterioscler. Thromb. Vasc. Biol. 29, 431-438
2. Hobbs, H. H., Brown, M. S., and Goldstein, J. L. (1992) Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum. Mutat. 1, 445-466
3. Innerarity, T. L., Mahley, R. W., Weisgraber, K. H., Bersot, T. P., Krauss, R. M., Vega, G. L., Grundy, S. M., Friedl, W., Davignon, J., and McCarthy, B. J. (1990) Familial defective apolipoprotein B-100. A mutation of apolipoprotein B that causes hypercholesterolemia. J. Lipid Res. 31, 1337-1349 (Pubitemid 20261898)
4. Abifadel, M., Rabès, J. P., Devillers, M., Munnich, A., Erlich, D., Junien, C., Varret, M., and Boileau, C. (2009) Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum. Mutat. 30, 520-529
5. Horton, J. D., Cohen, J. C., and Hobbs, H. H. (2009) PCSK9. A convertase that coordinates LDL catabolism. J. Lipid Res. 50, S172-S177
6. Seidah, N. G. (2009) PCSK9 as a therapeutic target of dyslipidemia. Expert. Opin. Ther. Targets 13, 19-28
7. Abifadel, M., Varret, M., Rabès, J. P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derré, A., Villéger, L., Farnier, M., Beucler, I., Bruckert, E., Chambaz, J., Chanu, B., Lecerf, J. M., Luc, G., Moulin, P., Weissenbach, J., Prat, A., Krempf, M., Junien, C., Seidah, N. G., and Boileau, C. (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154-156 (Pubitemid 36666925)
8. Seidah, N. G., Benjannet, S., Wickham, L., Marcinkiewicz, J., Jasmin, S. B., Stifani, S., Basak, A., Prat, A., and Chretien, M. (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, 928-933 (Pubitemid 36183932)
9. Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., and Hobbs, H. H. (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161-165
10. Cohen, J. C., Boerwinkle, E., Mosley, T. H., Jr., and Hobbs, H. H. (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264-1272
11. 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., and Seidah, N. G. (2004) NARC-1/PCSK9 and its natural mutants. Zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J. Biol. Chem. 279, 48865-48875 (Pubitemid 39625767)
12. Naureckiene, S., Ma, L., Sreekumar, K., Purandare, U., Lo, C. F., Huang, Y., Chiang, L. W., Grenier, J. M., Ozenberger, B. A., Jacobsen, J. S., Kennedy, J. D., DiStefano, P. S., Wood, A., and Bingham, B. (2003) Functional characterization of Narc 1, a novel proteinase related to proteinase K. Arch. Biochem. Biophys. 420, 55-67 (Pubitemid 37393374)
13. 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., and Qiu, X. (2007) Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat. Struct. Mol. Biol. 14, 413-419 (Pubitemid 46685885)
14. Piper, D. E., Jackson, S., Liu, Q., Romanow, W. G., Shetterly, S., Thibault, S. T., Shan, B., and Walker, N. P. (2007) The crystal structure of PCSK9. A regulator of plasma LDL-cholesterol. Structure 15, 545-552 (Pubitemid 46702689)
15. McNutt, M. C., Lagace, T. A., and Horton, J. D. (2007) Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells. J. Biol. Chem. 282, 20799-20803 (Pubitemid 47099894)
16. Grefhorst, A., McNutt, M. C., Lagace, T. A., and Horton, J. D. (2008) Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J. Lipid Res. 49, 1303-1311
17. Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., and Deisenhofer, J. (2008) Molecular basis for LDL receptor recognition by PCSK9. Proc. Natl. Acad. Sci. U.S.A. 105, 1820-1825 (Pubitemid 351439423)
18. Zhang, D.-W., Lagace, T. A., Garuti, R., Zhao, Z., McDonald, M., Horton, J. D., Cohen, J. C., and Hobbs, H. H. (2007) Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeatAof low density lipoprotein receptor decreases receptor recycling and increases degradation. J. Biol. Chem. 282, 18602-18612 (Pubitemid 47100234)
19. Maxwell, K. N., Soccio, R. E., Duncan, E. M., Sehayek, E., and Breslow, J. L. (2003) Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J. Lipid Res. 44, 2109-2119 (Pubitemid 37509626)
20. Horton, J. D., Shah, N. A., Warrington, J. A., Anderson, N. N., Park, S. W., Brown, M. S., and Goldstein, J. L. (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, 12027-12032 (Pubitemid 37271509)
21. Dubuc, G., Chamberland, A., Wassef, H., Davignon, J., Seidah, N. G., Bernier, L., and Prat, A. (2004) Statins up-regulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase- 1 implicated in familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 24, 1454-1459 (Pubitemid 39050440)
22. Careskey, H. E., Davis, R. A., Alborn, W. E., Troutt, J. S., Cao, G., and Konrad, R. J. (2008) Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J. Lipid Res. 49, 394-398 (Pubitemid 351213624)
23. Mayne, J., Dewpura, T., Raymond, A., Cousins, M., Chaplin, A., Lahey, K. A., Lahaye, S. A., Mbikay, M., Ooi, T. C., and Chrétien, M. (2008) Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis. 7, 22
24. Davignon, J., and Dubuc, G. (2009) Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans. Am. Clin. Climatol. Assoc. 120, 163-173
25. Frank-Kamenetsky, M., Grefhorst, A., Anderson, N. N., Racie, T. S., Bramlage, B., Akinc, A., Butler, D., Charisse, K., Dorkin, R., Fan, Y., Gamba- Vitalo, C., Hadwiger, P., Jayaraman, M., John, M., Jayaprakash, K. N., Maier, M., Nechev, L., Rajeev, K. G., Read, T., Röhl, I., Soutschek, J., Tan, P., Wong, J., Wang, G., Zimmermann, T., de Fougerolles, A., Vornlocher, H. P., Langer, R., Anderson, D. G., Manoharan, M., Koteliansky, V., Horton, J. D., and Fitzgerald, K. (2008) Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl. Acad. Sci. U.S.A. 105, 11915-11920
26. 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., and Jackson, S. M. (2009) A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc. Natl. Acad. Sci. U.S.A. 106, 9820-9825
27. Stein, E. A., Mellis, S., Yancopoulos, G. D., Stahl, N., Logan, D., Smith, W. B., Lisbon, E., Gutierrez, M., Webb, C., Wu, R., Du, Y., Kranz, T., Gasparino, E., and Swergold, G. D. (2012) Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366, 1108-1118
28. Lakoski, S. G., Lagace, T. A., Cohen, J. C., Horton, J. D., and Hobbs, H. H. (2009) Genetic and metabolic determinants of plasma PCSK9 levels. J. Clin. Endocrinol. Metab. 94, 2537-2543
29. Mayne, J., Raymond, A., Chaplin, A., Cousins, M., Kaefer, N., Gyamera- Acheampong, C., Seidah, N. G., Mbikay, M., Chrétien, M., and Ooi, T. C. (2007) Plasma PCSK9 levels correlate with cholesterol in men but not in women. Biochem. Biophys. Res. Commun. 361, 451-456 (Pubitemid 47193117)
30. Welder, G., Zineh, I., Pacanowski, M. A., Troutt, J. S., Cao, G., and Konrad, R. J. (2010) High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J. Lipid Res. 51, 2714-2721
31. Lambert, G., Ancellin, N., Charlton, F., Comas, D., Pilot, J., Keech, A., Patel, S., Sullivan, D. R., Cohn, J. S., Rye, K.-A., and Barter, P. J. (2008) Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment. Clin. Chem. 54, 1038-1045 (Pubitemid 351793411)
32. Browning, J. D., and Horton, J. D. (2010) Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9, and cholesterol biosynthesis in humans. J. Lipid Res. 51, 3359-3363
33. Persson, L., Cao, G., Ståhle, L., Sjöberg, B. G., Troutt, J. S., Konrad, R. J., Gälman, C., Wallén, H., Eriksson, M., Hafström, I., Lind, S., Dahlin, M., Amark, P., Angelin, B., and Rudling, M. (2010) Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans. Arterioscler. Thromb. Vasc. Biol. 30, 2666-2672
34. Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., and Seidah, N. G. (2006) The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A. Functional consequences of natural mutations and posttranslational modifications. J. Biol. Chem. 281, 30561-30572 (Pubitemid 44582112)
35. Fan, D., Yancey, P. G., Qiu, S., Ding, L., Weeber, E. J., Linton, M. F., and Fazio, S. (2008) Self-association of human PCSK9 correlates with its LDLR-degrading activity. Biochemistry 47, 1631-1639 (Pubitemid 351231213)
36. Luo, Y., Warren, L., Xia, D., Jensen, H., Sand, T., Petras, S., Qin, W., Miller, K. S., and Hawkins, J. (2009) Function and distribution of circulating human PCSK9 expressed extrahepatically in transgenic mice. J. Lipid Res. 50, 1581-1588
37. Brown, M. S., Faust, J. R., Goldstein, J. L., Kaneko, I., and Endo, A. (1978) Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase. J. Biol. Chem. 253, 1121-1128 (Pubitemid 8288831)
38. Goldstein, J. L., Basu, S. K., and Brown, M. S. (1983) Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 98, 241-260 (Pubitemid 14219888)
39. Russell, D. W., Brown, M. S., and Goldstein, J. L. (1989) Different combinations of cysteine-rich repeats mediate binding of low density lipoprotein receptor to two different proteins. J. Biol. Chem. 264, 21682-21688 (Pubitemid 20028736)
40. Lagace, T. A., Curtis, D. E., Garuti, R., McNutt, M. C., Park, S. W., Prather, H. B., Anderson, N. N., Ho, Y. K., Hammer, R. E., and Horton, J. D. (2006) Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J. Clin. Invest. 116, 2995-3005 (Pubitemid 44684484)
41. Havel, R. J., Eder, H. A., and Bragdon, J. H. (1955) The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J. Clin. Invest. 34, 1345-1353
42. Peterson, G. L. (1977) A simplification of the protein assay method of Lowry et al., which is more generally applicable. Anal. Biochem. 83, 346-356 (Pubitemid 8269786)
43. Yee, M. S., Pavitt, D. V., Tan, T., Venkatesan, S., Godsland, I. F., Richmond, W., and Johnston, D. G. (2008) Lipoprotein separation in a novel iodixanol density gradient, for composition, density, and phenotype analysis. J. Lipid Res. 49, 1364-1371
44. Benjannet, S., Saavedra, Y. G., Hamelin, J., Asselin, M. C., Essalmani, R., Pasquato, A., Lemaire, P., Duke, G., Miao, B., Duclos, F., Parker, R., Mayer, G., and Seidah, N. G. (2010) Effects of the prosegment and pH on the activity of PCSK9. Evidence for additional processing events. J. Biol. Chem. 285, 40965-40978
45. Marcel, Y. L., Hogue, M., Weech, P. K., Davignon, J., and Milne, R. W. (1988) Expression of apolipoprotein B epitopes in lipoproteins. Relationship to conformation and function. Arteriosclerosis 8, 832-844 (Pubitemid 19005372)
46. Boren, J., Lee, I., Zhu, W., Arnold, K., Taylor, S., and Innerarity, T. L. (1998) Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J. Clin. Invest. 101, 1084-1093 (Pubitemid 28125287)
47. Karlsson, H., Leanderson, P., Tagesson, C., and Lindahl, M. (2005) Proteomics 5, 551-565
48. Sun, H., Samarghandi, A., Zhang, N., Yao, Z., Xiong, M., and Teng, B. B. (2012) 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. 32, 1585-1595
49. Zhao, Z., Tuakli-Wosornu, Y., Lagace, T. A., Kinch, L., Grishin, N. V., Horton, J. D., Cohen, J. C., and Hobbs, H. H. (2006) Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am. J. Hum. Genet. 79, 514-523 (Pubitemid 44384260)
50. 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., and Sitlani, A. (2007) Effects of pH and low density lipoprotein (LDL) on PCSK9-dependent LDL receptor regulation. J. Biol. Chem. 282, 20502-20512 (Pubitemid 47100016)
51. Schneider, W. J., Beisiegel, U., Goldstein, J. L., and Brown, M. S. (1982) Purification of the low density lipoprotein receptor, an acidic glycoprotein of 164,000 molecular weight. J. Biol. Chem. 257, 2664-2673
52. Holla, Ø. L., Laerdahl, J. K., Strøm, T. B., Tveten, K., Cameron, J., Berge, K. E., and Leren, T. P. (2011) Removal of acidic residues of the prodomain of PCSK9 increases its activity toward the LDL receptor. Biochem. Biophys. Res. Commun. 406, 234-238