Secreted PCSK9 promotes LDL receptor degradation independently of proteolytic activity

Biochemical Journal

Volumn 406, Issue 2, 2007, Pages 203-207

  Li, Jun ^a   Tumanut, Christine ^a   Gavigan, Julie Ann ^a   Huang, Waan Jeng ^a   Hampton, Eric N ^a   Tumanut, Rachelle ^a   Suen, Ka Fai ^a   Trauger, John W ^a   Spraggon, Glen ^a   Lesley, Scott A ^a   Liau, Gene ^b   Yowe, David ^b   Harris, Jennifer L ^a  

^a GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION   (United States)

^b NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

Atherosclerosis; Coronary heart disease; Hypercholesterolaemia; Low density lipoprotein receptor (LDL R); Proprotein convertase subtilisin kexin 9 (PCSK9); trans assembly

Indexed keywords

ATHEROSCLEROSIS; CORONARY HEART DISEASE; HYPERCHOLESTEROLAEMIA; LOW DENSITY LIPOPROTEIN RECEPTOR (LDL-R); PROPROTEIN CONVERTASE SUBTILISIN/KEXIN 9 (PCSK9); TRANS-ASSEMBLY;

CATALYST ACTIVITY; CHOLESTEROL; COMPLEXATION; ENZYME ACTIVITY;

ENZYME KINETICS;

LOW DENSITY LIPOPROTEIN RECEPTOR; PROPROTEIN CONVERTASE SUBTILISIN KEXIN 9; SERINE PROTEINASE; UNCLASSIFIED DRUG;

ARTICLE; CATALYSIS; CONTROLLED STUDY; ENDOPLASMIC RETICULUM; HUMAN; HUMAN CELL; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN PURIFICATION;

CELL LINE; HUMANS; MUTATION; RECEPTORS, LDL; SERINE; SERINE ENDOPEPTIDASES;

EID: 34548163845     PISSN: 02646021     EISSN: None     Source Type: Journal    
DOI: 10.1042/BJ20070664     Document Type: Article

References (24)

1. 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
2. Abifadel, M., Varret, M., Rabes, J. P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D. et al. (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154-156
3. Shioji, K., Mannami, T., Kokubo, Y., Inamoto, N., Takagi, S., Goto, Y., Nonogi, H. and Iwai, N. (2004) Genetic variants in PCSK9 affect the cholesterol level in Japanese. J. Hum. Genet. 49, 109-114
4. Timms, K. M., Wagner, S., Samuels, M. E., Forbey, K., Goldfine, H., Jammulapati, S., Skolnick, M. H., Hopkins, P. N., Hunt, S. C. and Shattuck, D. M. (2004) A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum. Genet. 114, 349-353
5. Leren, T. P. (2004) Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin. Genet. 65, 419-422
6. Cohen, J. C., Boerwinkle, E., Mosley, Jr, T. H. and Hobbs, H. H. (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264-1272
7. Rashid, S., Curtis, D. E., Garuti, R., Anderson, N. N., Bashmakov, Y., Ho, Y. K., Hammer, R. E., Moon, Y. A. and Horton, J. D. (2005) Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Natl. Acad. Sci. U.S.A. 102, 5374-5379
8. 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
9. Maxwell, K. N. and Breslow, J. L. (2004) Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc. Natl. Acad. Sci. U.S.A. 101, 7100-7105
10. 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
11. Seidah, N. G. and Prat, A. (2007) The proprotein convertases are potential targets in the treatment of dyslipidemia. J. Mol. Med., doi:10.1007/s00109-007-0172-7
12. Park, S. W., Moon, Y. A. and Horton, J. D. (2004) Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J. Biol. Chem. 279, 50630-50638
13. Benjannet, S., Rhainds, D., Essalmani, R., Mayne, J., Wickham, L., Jin, W., Asselin, M. C., Hamelin, J., Varret, M., Allard, D. et al. (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
14. 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. et al. (2007) Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat. Struct. Mol. Biol. 14, 413-419
15. 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
16. Cameron, J., Holla, O. L., Ranheim, T., Kulseth, M. A., Berge, K. E. and Leren, T. P. (2006) Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Hum. Mol. Genet. 15, 1551-1558
17. Baker, D., Shiau, A. K. and Agard, D. A. (1993) The role of pro regions in protein folding. Curr. Opin. Cell Biol. 5, 966-970
18. Silen, J. L. and Agard, D. A. (1989) The α-lytic protease pro-region does not require a physical linkage to activate the protease domain in vivo. Nature 341, 462-464
19. Zhu, X. L., Ohta, Y., Jordan, F. and Inouye, M. (1989) Pro-sequence of subtilisin can guide the refolding of denatured subtilisin in an intermolecular process. Nature 339, 483-484
20. Brown, M. S., Herz, J. and Goldstein, J. L. (1997) LDL-receptor structure: calcium cages, acid baths and recycling receptors. Nature 388, 629-630
21. 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. et al. (2007) PCSK9-dependent LDL receptor regulation: effects of pH and LDL. J. Biol. Chem. 282, 20502-20512
22. 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 PCSK9 to EGF-A repeat of LDL receptor decreases receptor recycling and increases degradation. J. Biol. Chem. 282, 18602-18612
23. Maxwell, K. N., Fisher, E. A. and Breslow, J. L. (2005) Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc. Natl. Acad. Sci. U.S.A. 102, 2069-2074
24. McNutt, M. C., Lagace, T. A. and Horton, J. D. (2007) Catalytic activity is not required for secreted PCSK9 to reduce LDL receptors in HepG2 cells. J. Biol. Chem., doi:10.1074/jbc.C700095200