| Structural highlights
Disease
[PCSK9_HUMAN] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:603776]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.[1] [LDLR_HUMAN] Defects in LDLR are the cause of familial hypercholesterolemia (FH) [MIM:143890]; a common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis).[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [:][33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44]
Function
[PCSK9_HUMAN] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.[45] [46] [47] [48] [49] [50] [51] [LDLR_HUMAN] Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. In case of HIV-1 infection, functions as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells.
Publication Abstract from PubMed
The protein PCSK9 (proprotein convertase subtilisin/kexin type 9) is a key regulator of low-density lipoprotein receptor (LDLR) levels and cardiovascular health. We have determined the crystal structure of LDLR bound to PCSK9 at neutral pH. The structure shows LDLR in a new extended conformation. The PCSK9 C-terminal domain is solvent exposed, enabling cofactor binding, whereas the catalytic domain and prodomain interact with LDLR epidermal growth factor(A) and beta-propeller domains, respectively. Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling.
Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH.,Lo Surdo P, Bottomley MJ, Calzetta A, Settembre EC, Cirillo A, Pandit S, Ni YG, Hubbard B, Sitlani A, Carfi A EMBO Rep. 2011 Dec 1;12(12):1300-5. doi: 10.1038/embor.2011.205. PMID:22081141[52]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Rubinsztein DC, Jialal I, Leitersdorf E, Coetzee GA, van der Westhuyzen DR. Identification of two new LDL-receptor mutations causing homozygous familial hypercholesterolemia in a South African of Indian origin. Biochim Biophys Acta. 1993 Aug 4;1182(1):75-82. PMID:8347689
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- ↑ Soutar AK, Knight BL, Patel DD. Identification of a point mutation in growth factor repeat C of the low density lipoprotein-receptor gene in a patient with homozygous familial hypercholesterolemia that affects ligand binding and intracellular movement of receptors. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4166-70. PMID:2726768
- ↑ Rubinsztein DC, Coetzee GA, Marais AD, Leitersdorf E, Seftel HC, van der Westhuyzen DR. Identification and properties of the proline664-leucine mutant LDL receptor in South Africans of Indian origin. J Lipid Res. 1992 Nov;33(11):1647-55. PMID:1464748
- ↑ Koivisto UM, Viikari JS, Kontula K. Molecular characterization of minor gene rearrangements in Finnish patients with heterozygous familial hypercholesterolemia: identification of two common missense mutations (Gly823-->Asp and Leu380-->His) and eight rare mutations of the LDL receptor gene. Am J Hum Genet. 1995 Oct;57(4):789-97. PMID:7573037
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- ↑ Jensen HK, Jensen TG, Faergeman O, Jensen LG, Andresen BS, Corydon MJ, Andreasen PH, Hansen PS, Heath F, Bolund L, Gregersen N. Two mutations in the same low-density lipoprotein receptor allele act in synergy to reduce receptor function in heterozygous familial hypercholesterolemia. Hum Mutat. 1997;9(5):437-44. PMID:9143924 doi:<437::AID-HUMU10>3.0.CO;2-3 10.1002/(SICI)1098-1004(1997)9:5<437::AID-HUMU10>3.0.CO;2-3
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- ↑ Cenarro A, Jensen HK, Casao E, Civeira F, Gonzalez-Bonillo J, Rodriguez-Rey JC, Gregersen N, Pocovi M. Identification of recurrent and novel mutations in the LDL receptor gene in Spanish patients with familial hypercholesterolemia. Mutations in brief no. 135. Online. Hum Mutat. 1998;11(5):413. PMID:10206683 doi:<413::AID-HUMU16>3.0.CO;2-I 10.1002/(SICI)1098-1004(1998)11:5<413::AID-HUMU16>3.0.CO;2-I
- ↑ Motti C, Bertolini S, Rampa P, Trovatello G, Liberatoscioli L, Calandra S, Federici G, Cortese C. Two novel mutations consisting in minor gene rearrangements in the human low density lipoprotein receptor gene in Italian patients affected by familial hypercholesterolemia. Mutations in brief no. 194. Online. Hum Mutat. 1998;12(3):290. PMID:10660340
- ↑ Hirayama T, Yamaki E, Hata A, Tsuji M, Hashimoto K, Yamamoto M, Emi M. Five familial hypercholesterolemic kindreds in Japan with novel mutations of the LDL receptor gene. J Hum Genet. 1998;43(4):250-4. PMID:9852677 doi:10.1007/s100380050083
- ↑ Lee WK, Haddad L, Macleod MJ, Dorrance AM, Wilson DJ, Gaffney D, Dominiczak MH, Packard CJ, Day IN, Humphries SE, Dominiczak AF. Identification of a common low density lipoprotein receptor mutation (C163Y) in the west of Scotland. J Med Genet. 1998 Jul;35(7):573-8. PMID:9678702
- ↑ Ekstrom U, Abrahamson M, Floren CH, Tollig H, Wettrell G, Nilsson G, Sun XM, Soutar AK, Nilsson-Ehle P. An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F). Clin Genet. 1999 May;55(5):332-9. PMID:10422803
- ↑ Ebhardt M, Schmidt H, Doerk T, Tietge U, Haas R, Manns MP, Schmidtke J, Stuhrmann M. Mutation analysis in 46 German families with familial hypercholesterolemia: identification of 8 new mutations. Mutations in brief no. 226. Online. Hum Mutat. 1999;13(3):257. PMID:10090484 doi:<257::AID-HUMU15>3.0.CO;2-A 10.1002/(SICI)1098-1004(1999)13:3<257::AID-HUMU15>3.0.CO;2-A
- ↑ Hattori H, Nagano M, Iwata F, Homma Y, Egashira T, Okada T. Identification of recurrent and novel mutations in the LDL receptor gene in Japanese familial hypercholesterolemia. Mutation in brief no. 248. Online. Hum Mutat. 1999;14(1):87. PMID:10447263 doi:<87::AID-HUMU14>3.0.CO;2-N 10.1002/(SICI)1098-1004(1999)14:1<87::AID-HUMU14>3.0.CO;2-N
- ↑ Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, Pes G, Postiglione A, Stefanutti C, Blotta I, Pisciotta L, Rolleri M, Langheim S, Ghisellini M, Rabbone I, Calandra S. Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype. Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E41-52. PMID:10978268
- ↑ Miltiadous G, Elisaf M, Xenophontos S, Manoli P, Cariolou MA. Segregation of a novel LDLR gene mutation (I430T) with familial hypercholesterolaemia in a Greek pedigree. Hum Mutat. 2000 Sep;16(3):277. PMID:10980548 doi:<277::AID-HUMU24>3.0.CO;2-Y 10.1002/1098-1004(200009)16:3<277::AID-HUMU24>3.0.CO;2-Y
- ↑ Thiart R, Scholtz CL, Vergotine J, Hoogendijk CF, de Villiers JN, Nissen H, Brusgaard K, Gaffney D, Hoffs MS, Vermaak WJ, Kotze MJ. Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia. J Med Genet. 2000 Jul;37(7):514-9. PMID:10882754
- ↑ Takahashi M, Ikeda U, Takahashi S, Hattori H, Iwasaki T, Ishihara M, Egashira T, Honma S, Asano Y, Shimada K. A novel mutation in exon 2 of the low-density lipoprotein-receptor gene in a patient with homozygous familial hypercholesterolemia. Clin Genet. 2001 Apr;59(4):290-2. PMID:11298688
- ↑ Humphries SE, Whittall RA, Hubbart CS, Maplebeck S, Cooper JA, Soutar AK, Naoumova R, Thompson GR, Seed M, Durrington PN, Miller JP, Betteridge DJ, Neil HA. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet. 2006 Dec;43(12):943-9. PMID:17142622 doi:10.1136/jmg.2006.038356
- ↑ Abifadel M, Rabes JP, Jambart S, Halaby G, Gannage-Yared MH, Sarkis A, Beaino G, Varret M, Salem N, Corbani S, Aydenian H, Junien C, Munnich A, Boileau C. The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene. Hum Mutat. 2009 Jul;30(7):E682-91. doi: 10.1002/humu.21002. PMID:19319977 doi:10.1002/humu.21002
- ↑ Walus-Miarka M, Sanak M, Idzior-Walus B, Miarka P, Witek P, Malecki MT, Czarnecka D. A novel mutation (Cys308Phe) of the LDL receptor gene in families from the South-Eastern part of Poland. Mol Biol Rep. 2012 May;39(5):5181-6. doi: 10.1007/s11033-011-1314-0. Epub 2011, Dec 13. PMID:22160468 doi:10.1007/s11033-011-1314-0
- ↑ Nassoury N, Blasiole DA, Tebon Oler A, Benjannet S, Hamelin J, Poupon V, McPherson PS, Attie AD, Prat A, Seidah NG. The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic. 2007 Jun;8(6):718-32. Epub 2007 Apr 25. PMID:17461796 doi:10.1111/j.1600-0854.2007.00562.x
- ↑ Fan D, Yancey PG, Qiu S, Ding L, Weeber EJ, Linton MF, Fazio S. Self-association of human PCSK9 correlates with its LDLR-degrading activity. Biochemistry. 2008 Feb 12;47(6):1631-9. doi: 10.1021/bi7016359. Epub 2008 Jan 16. PMID:18197702 doi:10.1021/bi7016359
- ↑ Jonas MC, Costantini C, Puglielli L. PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep. 2008 Sep;9(9):916-22. doi: 10.1038/embor.2008.132. Epub 2008 Jul 25. PMID:18660751 doi:10.1038/embor.2008.132
- ↑ Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, Nassoury N, Mayer H, Nimpf J, Prat A, Seidah NG. 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 Jan 25;283(4):2363-72. Epub 2007 Nov 26. PMID:18039658 doi:10.1074/jbc.M708098200
- ↑ Chen Y, Wang H, Yu L, Yu X, Qian YW, Cao G, Wang J. Role of ubiquitination in PCSK9-mediated low-density lipoprotein receptor degradation. Biochem Biophys Res Commun. 2011 Nov 25;415(3):515-8. doi:, 10.1016/j.bbrc.2011.10.110. Epub 2011 Nov 2. PMID:22074827 doi:10.1016/j.bbrc.2011.10.110
- ↑ Sun H, Samarghandi A, Zhang N, Yao Z, Xiong M, Teng BB. 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 Jul;32(7):1585-95. doi:, 10.1161/ATVBAHA.112.250043. Epub 2012 May 10. PMID:22580899 doi:10.1161/ATVBAHA.112.250043
- ↑ Sharotri V, Collier DM, Olson DR, Zhou R, Snyder PM. Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). J Biol Chem. 2012 Jun 1;287(23):19266-74. doi: 10.1074/jbc.M112.363382. Epub 2012, Apr 9. PMID:22493497 doi:10.1074/jbc.M112.363382
- ↑ Lo Surdo P, Bottomley MJ, Calzetta A, Settembre EC, Cirillo A, Pandit S, Ni YG, Hubbard B, Sitlani A, Carfi A. Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. EMBO Rep. 2011 Dec 1;12(12):1300-5. doi: 10.1038/embor.2011.205. PMID:22081141 doi:https://dx.doi.org/10.1038/embor.2011.205
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