PCSK9 Molecule: Characteristics and Clinical Importance
Authors:
T. Vacková 1,2; J. Franeková 1,2; A. Jabor 1,2
Authors‘ workplace:
Oddělení klinické biochemie, Pracoviště laboratorních metod, Institut klinické a experimentální medicíny, Praha
1; Univerzita Karlova, 3. lékařská fakulta, Praha
2
Published in:
Klin. Biochem. Metab., 27, 2019, No. 4, p. 177-182
Overview
Objective: Introducing the proprotein convertase subtilisin/kexin type 9 (PCSK9/NARC1) molecule, which significantly participates in lipid metabolism, to describe its chemical structure and properties, its role in metabolism and last but not least its clinical significance.
Design: literature review.
Settings: Institute for Clinical and Experimental Medicine, Vídeňská 1958/9, 140 21 Praha 4
Conclusion: Due to its important role in lipid metabolism, the PCSK9 molecule becomes a very interesting and important analyte across clinical disciplines.
Keywords:
domain – Mutation – PCSK9 – LDLR – lipid metabolism – degradation
Sources
1. Seidah, N. G., Chrétien, M., Day, R. The family of subtilisin/kexin like pro-protein and pro-hormone convertases: Divergent or shared functions. Biochimie, 1994, Vol. 76(3-4), p. 197-209.
2. Seidah, N. G., Prat, A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov., 2012, Vol. 11(5), p. 367-383.
3. Artenstein, A. W., Opal, S. M. Proprotein convertases in health and disease. N Engl J Med., 2011, Vol. 365(26), p. 2507-2518.
4. Seidah, N. G., Prat, A. The proprotein convertases are potential targets in the treatment of dyslipidemia. J Mol Med., 2007, Vol. 85(7), p. 685-696.
5. Wiciński, M., Źak, J., Malinowski, B., Popek, G., Grześk, G. PCSK9 signaling pathways and their potential importance in clinical practice. EPMA J., 2017, Vol. 8(4), p. 391-402.
6. OMIM. An Online Catalog of Human Genes and Genetic Disorders. Dostupné z WWW: https://omim.org/entry/607786, https://omim.org/entry606945?search=606945&highlight=606945, https://omim.org/entry605747?search=605747&highlight=605747
7. Benjannet, S., Rhainds, D., Essalmani, R., et al. 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, Vol. 279(47), p. 48865-48875.
8. Seidah, N. G., Awan, Z., Chrétien, M., Mbikay, M. PCSK9: a key modulator of cardiovascular health. Circ Res., 2014, Vol. 114(6), p. 1022-1036.
9. Cunningham, D., Danley, D. E., Geoghegan, K. F., et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Mol Biol., 2007, Vol. 14(5), p. 413-419.
10. Piper, D. E., Jackson, S., Liu, Q., et al. The Crystal Structure of PCSK9: A Regulator of Plasma LDL-Cholesterol. Structure, 2007, Vol. 15(5), p. 545-552.
11. Nishikido, T., Ray, K. K. Non-antibody approaches to proprotein convertase subtilisin kexin 9 inhibition: siRNA, antisense oligonucleotides, adnectins, vaccination, and new attempts at small-molecule inhibitors based on new discoveries. Front Cardiovasc Med., 2019, Vol. 5, p. 1-17.
12. 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 Å reveals structural homology with resistin within the C-terminal domain. Proc Natl Acad Sci USA, 2007, Vol. 104(37), p. 14604-14609.
13. 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, Vol. 105(6), p. 1820-1825.
14. Benjannet, S., Hamelin, J., Chrétien, M., Seidah, N. G. Loss- and gain-of-function PCSK9 variants: cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation. J Biol Chem., 2012, Vol. 287(40), p. 33745-33755.
15. Seidah, N. G., Benjannet, S., Wickham, L., et al. The secretory proprotein convertase 1 (NARC-1): Liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA, 2003, Vol. 100(3), p. 928-933.
16. Lagace, T. A., Curtis, D. E., Garuti, R., et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. The J Clin Invest., 2006, Vol. 116(11), p. 2995-3005.
17. Han, B., Eacho, P. I., Knierman M. D., et al. Isolation and characterization of the circulating truncated form of PCSK9. J Lipid Res., 2014, Vol. 55(7), p. 1505-1514.
18. Melendez, Q. M., Krishnaji, S. T., Wooten, C. J., Lopez, D. Hypercholesterolemia: The role of PCSK9. Arch Biochem Biophys., 2017, Vol. 625-626, p. 39-53.
19. Yamamoto, T., Davis, C. G., Brown, M. S., et al. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell, 1984, Vol. 39(1), p. 27-38.
20. Russel, D. W., Brown, M. S., Goldstein, J. L. Different combinations of cysteine-rich repeats mediate binding of low density lipoprotein receptor to two different proteins. J Biol Chem., 1989, Vol. 264(36), p. 21682-21688.
21. Tolleshaug, H., Goldstein, J. L., Schneider, W. J., Brown, M. S. Posttranslational processing of the LDL receptor and its genetic disruption in familial hypercholesterolemia. Cell, 1982, Vol. 30(3), p. 715-724.
22. Poirier, S. Mayer, G., Poupon, V., et al. Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route. J Biol Chem., 2009, Vol. 284(42), p. 28856-28864.
23. Maxwell, K. N., Fisher, E. A., Breslow, J. L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA, 2005, Vol. 102(6), p. 2069-2074.
24. Zhang, D. W., Garuti, R., Tang, W. J., Cohen, J. C., Hobbs, H. H. Structural requirements for PCSK9-media-ted degradation of the low-density lipoprotein receptor. Proc Natl Acad Sci USA, 2008, Vol. 105(35), p. 13045-13050.
25. Chen, W. J., Goldstein, J. L., Brown, M. S. NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J Biol Chem., 1990, Vol. 265(6), p. 3116-3123.
26. Gent, J., Braakman, I. Low-density lipoprotein receptor structure and folding. Cell Mol Life Sci., 2004, Vol. 61(19-20), p. 2461-2470.
27. Garuti, R., Jones, Ch., Li, W. P., et al. The modular adaptor protein autosomal recessive hypercholestero-lemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits. J Biol Chem., 2005, Vol. 280(49), p. 40996-41004.
28. Rudenko, G., Henry, L., Henderson, K., et al. Structure of the LDL receptor extracellular domain at endosomal pH. Science, 2002, Vol. 298(5602), p. 2353-2358.
29. Zhang, D. W., Lagace, T. A., Garuti, R., et al. Bin-ding 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, Vol. 282(25), p. 18602-18612.
30. Fan, D., Yancey, P. G., Qiu, S., et al. Self-association of human PCSK9 correlates with its LDLR-degrading activity. Biochemistry, 2008, Vol. 47(6), p. 1-22.
31. Sun, H., Samarghandi, A., Zhang, N., Yao, Z., Xiong, M., Teng, B. B. 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, Vol. 32(7), p. 1585-1595.
32. Gillian-Daniel, D. L., Bates, P. W., Tebon, A., Attie, A. D. Endoplasmic reticulum localization of the low density lipoprotein receptor mediates presecretory degradation of apolipoprotein B. Proc Natl Acad Sci USA, 2002, Vol. 99(7), p. 4337-4342.
33. Fisher, E. A., Ginsberg H. N. Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins. J Biol Chem, 2002, Vol. 277(20), p. 17377-17380.
34. Pandit, S., Wisniewski, D., Santoro, J. C., et al. Functional analysis of sites within PCSK9 responsible for hypercholesterolemia. J Lipid Res., 2008, Vol. 49(6), p. 1333-1343.
Labels
Clinical biochemistry Nuclear medicine Nutritive therapistArticle was published in
Clinical Biochemistry and Metabolism
2019 Issue 4
Most read in this issue
- Hypernatremia – Frequency, Causes, Pathobiochemistry, Clinic and Therapy
- Oxysterols - biochemistry and clinical importance
- Non-specific and ambiguous positive laboratory findings
- Macro-complexes and possibilities of their detection