PCSK9: A convertase that coordinates LDL catabolism

Journal of Lipid Research

Volumn 50, Issue SUPPL., 2009, Pages

  Horton, Jay D ^a   Cohen, Jonathan C ^a   Hobbs, Helen H ^a,b  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

Hypercholesterolemia; Low density lipoprotein; Low density lipoprotein receptor; Proprotein convertase subtilisin like kexin type 9

Indexed keywords

LOW DENSITY LIPOPROTEIN CHOLESTEROL; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR;

ANIMAL; APOPTOSIS; ARTICLE; CHEMISTRY; GENETICS; HUMAN; METABOLISM; PROTEIN BINDING; TRANSPORT AT THE CELLULAR LEVEL;

ANIMALS; APOPTOSIS; BIOLOGICAL TRANSPORT; CHOLESTEROL, LDL; HUMANS; PROTEIN BINDING; SERINE ENDOPEPTIDASES; SERINE PROTEINASE INHIBITORS;

EID: 66349126280     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.R800091-JLR200     Document Type: Review

References (48)

1. Abifadel, M., M. Varret, J. P. Rabes, D. Allard, K. Ouguerram, M. Devillers, C. Cruaud, S. Benjannet, L. Wickham, D. Erlich, et al. 2003. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34: 154-156. (Pubitemid 36666925)
2. Zaid, A., A. Roubtsova, R. Essalmani, J. Marcinkiewicz, A. Chamberland, J. Hamelin, M. Tremblay, H. Jacques, W. Jin, J. Davignon, et al. 2008. Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology. 48: 646-654.
3. Horton, J. D., J. C. Cohen, and H. H. Hobbs. 2007. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem. Sci. 32: 71-77. (Pubitemid 46199197)
4. Seidah, N. G., S. Benjannet, L. Wickham, J. Marcinkiewicz, S. B. Jasmin, S. Stifani, A. Basak, A. Prat, and M. Chretien. 2003. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA. 100: 928-933. (Pubitemid 36183932)
5. Dewpura, T., A. Raymond, J. Hamelin, N. G. Seidah, M. Mbikay, M. Chretien, and J. Mayne. 2008. PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans. FEBS J. 275: 3480-3493. (Pubitemid 351813558)
6. Benjannet, S., D. Rhainds, J. Hamelin, N. Nassoury, and N. G. Seidah. 2006. The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications. J. Biol. Chem. 281: 30561-30572. (Pubitemid 44582112)
7. Mayne, J., T. Dewpura, A. Raymond, M. Cousins, A. Chaplin, K. A. Lahey, S. A. Lahaye, M. Mbikay, T. C. Ooi, and M. Chretien. 2008. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis. 7: 22.
8. Careskey, H. E., R. A. Davis, W. E. Alborn, J. S. Troutt, G. Cao, and R. J. Konrad. 2008. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J. Lipid Res. 49: 394-398. (Pubitemid 351213624)
9. Lambert, G., N. Ancellin, F. Charlton, D. Comas, J. Pilot, A. Keech, S. Patel, D. R. Sullivan, J. S. Cohn, K. A. Rye, et al. 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)
10. Grefhorst, A., M. C. McNutt, T. A. Lagace, and J. D. Horton. 2008. Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J. Lipid Res. 49: 1303-1311.
11. Maxwell, K. N., E. A. Fisher, and J. L. Breslow. 2005. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc. Natl. Acad. Sci. USA. 102: 2069-2074. (Pubitemid 40262013)
12. Schmidt, R. J., T. P. Beyer, W. R. Bensch, Y. W. Qian, A. Lin, M. Kowala, W. E. Alborn, R. J. Konrad, and G. Cao. 2008. Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo. Biochem. Biophys. Res. Commun. 370: 634-640.
13. Brown, M. S., and J. L. Goldstein. 2008. Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL. J. Lipid Res. S15-S27.
14. Jeong, H. J., H. S. Lee, K. S. Kim, Y. K. Kim, D. Yoon, and S. W. Park. 2008. Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J. Lipid Res. 49: 399-409. (Pubitemid 351213625)
15. Costet, P., B. Cariou, G. Lambert, F. Lalanne, B. Lardeux, A. L. Jarnoux, A. Grefhorst, B. Staels, and M. Krempf. 2006. Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. J. Biol. Chem. 281: 6211-6218. (Pubitemid 43847551)
16. Langhi, C., C. Le May, S. Kourimate, S. Caron, B. Staels, M. Krempf, P. Costet, and B. Cariou. 2008. Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. FEBS Lett. 582: 949-955.
17. Kourimate, S., C. Le May, C. Langhi, A. L. Jarnoux, K. Ouguerram, Y. Zair, P. Nguyen, M. Krempf, B. Cariou, and P. Costet. 2008. Dual mechanisms for the fibrate-mediated repression of proprotein convertase subtilisin/kexin type 9. J. Biol. Chem. 283: 9666-9673.
18. Rudenko, G., L. Henry, K. Henderson, K. Ichtchenko, M. S. Brown, J. L. Goldstein, and J. Deisenhofer. 2002. Structure of the LDL receptor extracellular domain at endosomal pH. Science. 298: 2353-2358. (Pubitemid 36014201)
19. Zhang, D. W., T. A. Lagace, R. Garuti, Z. Zhao, M. McDonald, J. D. Horton, J. C. Cohen, and H. H. Hobbs. 2007. Binding of proprotein convertase subtilisin/kexin yype 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J. Biol. Chem. 282: 18602-18612. (Pubitemid 47100234)
20. Zhang, D. W., R. Garuti, W. J. Tang, J. C. Cohen, and H. H. Hobbs. 2008. Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor. Proc. Natl. Acad. Sci. USA. 105:13045-13050.
21. Cunningham, D., D. E. Danley, K. F. Geoghegan, M. C. Griffor, J. L. Hawkins, T. A. Subashi, A. H. Varghese, M. J. Ammirati, J. S. Culp, L. R. Hoth, et al. 2007. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat. Struct. Mol. Biol. 14: 413-419. (Pubitemid 46685885)
22. Fisher, T. S., P. Lo Surdo, S. Pandit, M. Mattu, J. C. Santoro, D. Wisniewski, R. T. Cummings, A. Calzetta, R. M. Cubbon, P. A. Fischer, et al. 2007. Effects of pH and low density lipoprotein (LDL) on PCSK9-dependent LDL receptor regulation. J. Biol. Chem. 282: 20502-20512. (Pubitemid 47100016)
23. Hampton, E. N., M. W. Knuth, J. Li, J. L. Harris, S. A. Lesley, and G. Spraggon. 2007. The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain. Proc. Natl. Acad. Sci. USA. 104: 14604-14609. (Pubitemid 350003191)
24. Piper, D. E., S. Jackson, Q. Liu, W. G. Romanow, S. Shetterly, S. T. Thibault, B. Shan, and N. P. Walker. 2007. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure. 15: 545-552. (Pubitemid 46702689)
25. Kwon, H. J., T. A. Lagace, M. C. McNutt, J. D. Horton, and J. Deisenhofer. 2008. Molecular basis for LDL receptor recognition by PCSK9. Proc. Natl. Acad. Sci. USA. 105: 1820-1825. (Pubitemid 351439423)
26. McNutt, M. C., T. A. Lagace, and J. D. Horton. 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)
27. Poirier, S., G. Mayer, S. Benjannet, E. Bergeron, J. Marcinkiewicz, N. Nassoury, H. Mayer, J. Nimpf, A. Prat, and N. G. Seidah. 2008. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J. Biol. Chem. 283: 2363-2372.
28. Humphries, S. E., R. A. Whittall, C. S. Hubbart, S. Maplebeck, J. A. Cooper, A. K. Soutar, R. Naoumova, G. R. Thompson, M. Seed, P. N. Durrington, et al. 2006. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J. Med. Genet. 43: 943-949. (Pubitemid 46080192)
29. Bottomley, M. J., A. Cirillo, L. Orsatti, L. Ruggeri, T. S. Fisher, J. C. Santoro, R. T. Cummings, R. M. Cubbon, P. Lo Surdo, A. Calzetta, et al. 2009. Structural and biochemical characterization of the wild type PCSK9/EGF(AB) complex and natural familial hypercholesterolemia mutants. J. Biol. Chem. 284: 1313-1323.
30. Pandit, S., D. Wisniewski, J. C. Santoro, S. Ha, V. Ramakrishnan, R. M. Cubbon, R. T. Cummings, S. D. Wright, C. P. Sparrow, A. Sitlani, et al. 2008. Functional analysis of sites within PCSK9 responsible for hypercholesterolemia. J. Lipid Res. 49: 1333-1343.
31. Bourbon, M., A. C. Alves, A. M. Medeiros, S. Silva, and A. K. Soutar. 2008. Familial hypercholesterolaemia in Portugal. Atherosclerosis. 196: 633-642.
32. Naoumova, R. P., I. Tosi, D. Patel, C. Neuwirth, S. D. Horswell, A. D. Marais, C. van Heyningen, and A. K. Soutar. 2005. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler. Thromb. Vasc. Biol. 25: 2654-2660. (Pubitemid 43732293)
33. Cameron, J., O. L. Holla, J. K. Laerdahl, M. A. Kulseth, T. Ranheim, T. Rognes, K. E. Berge, and T. P. Leren. 2008. Characterization of novel mutations in the catalytic domain of the PCSK9 gene. J. Intern. Med. 263: 420-431. (Pubitemid 351342682)
34. Homer, V. M., A. D. Marais, F. Charlton, A. D. Laurie, N. Hurndell, R. Scott, F. Mangili, D. R. Sullivan, P. J. Barter, K. A. Rye, et al. 2008. Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa. Atherosclerosis. 196: 659-666.
35. McPherson, R., and N. Kavaslar. 2007. Statins for primary prevention of coronary artery disease. Lancet. 369: 1078. (Pubitemid 46483653)
36. Kathiresan, S. 2008. APCSK9 missense variant associated witha reduced risk of early-onset myocardial infarction. N. Engl. J. Med. 358: 2299-2300. (Pubitemid 351724483)
37. Willer, C. J., S. Sanna, A. U. Jackson, A. Scuteri, L. L. Bonnycastle, R. Clarke, S. C. Heath, N. J. Timpson, S. S. Najjar, H. M. Stringham, et al. 2008. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40: 161-169. (Pubitemid 351171403)
38. Folsom, A. R., J. M. Peacock, and E. Boerwinkle. 2007. Sequence variation in proprotein convertase subtilisin/kexin type 9 serine protease gene, low LDL cholesterol, and cancer incidence. Cancer Epidemiol. Biomarkers Prev. 16: 2455-2458. (Pubitemid 351196380)
39. Hooper, A. J., A. D. Marais, D. M. Tanyanyiwa, and J. R. Burnett. 2007. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis. 193: 445-448. (Pubitemid 47058112)
40. Graham, M. J., K. M. Lemonidis, C. P. Whipple, A. Subramaniam, B. P. Monia, S. T. Crooke, and R. M. Crooke. 2007. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res. 48: 763-767. (Pubitemid 46557881)
41. Frank-Kamenetsky, M., A. Grefhorst, N. N. Anderson, T. S. Racie, B. Bramlage, A. Akinc, D. Butler, K. Charisse, R. Dorkin, Y. Fan, et al. 2008. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl. Acad. Sci. USA. 105: 11915-11920.
42. Qian, Y. W., R. J. Schmidt, Y. Zhang, S. Chu, A. Lin, H. Wang, X. Wang, T. P. Beyer, W. R. Bensch, W. Li, et al. 2007. Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J. Lipid Res. 48: 1488-1498. (Pubitemid 47312011)
43. Shan, L., L. Pang, R. Zhang, N. J. Murgolo, H. Lan, and J. A. Hedrick. 2008. PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide. Biochem. Biophys. Res. Commun. 375: 69-73.
44. Jones, P. H., M. H. Davidson, E. A. Stein, H. E. Bays, J. M. McKenney, E. Miller, V. A. Cain, and J. W. Blasetto; STELLAR Study Group. 2003. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin and pravastatin across doses (STELLER*Trial). Am. J. Cardiol. 92: 152-160. (Pubitemid 36835963)
45. Hallman, D. M., S. R. Srinivasan, W. Chen, E. Boerwinkle, and G. S. Berenson. 2007. Relation of PCSK9 mutations to serum low-density lipoprotein cholesterol in childhood and adulthood (from The Bogalusa Heart Study). Am. J. Cardiol. 100: 69-72. (Pubitemid 46961903)
46. Goldstein, J. L., H. H. Hobbs, and M. S. Brown. 2001. Familial hypercholesterolemia. In The Metabolic and Molecular Bases of Inherited Disease. C. Scriver, A. Beaudet, W. Sly, and D. Valle, editors. McGraw Hill, New York. 2863-2913.
47. Third report of the National Cholesterol Education Program (NCEP) expert panel on the detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation. 2002. 106: 3143-3421.
48. Hickman, T. B., R. R. Briefel, M. D. Carroll, B. M. Rifkind, J. I. Cleeman, K. R. Maurer, and C. L. Johnson. 1998. Distributions and trends of serum lipid levels among United States children and adolescents ages 4-19 years: data from the Third National Health and Nutrition Examination Survey. Prev. Med. 27: 879-890. (Pubitemid 29010857)