PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology
Abstract
:1. Introduction
2. PCSK9 Biology
3. PCSK9-LDLR Binding
4. PCSK9′s Activity Independent of LDLR
4.1. Inflammation and Atherosclerosis
4.2. Myocardial Infarction
4.3. Obesity Induced CVD
4.4. Calcification
5. PCSK9 Polymorphisms
6. PCSK9 Activators/Inhibitors
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Name of Mutation + Reference | Cause and Consequences |
---|---|
A443T [121,122] | Presence of a novel PCSK9 O-glycosylation site in the hinge region that promotes furin-cleavage and generates lower circulating levels of LDL-C and lower levels of fasting glucose |
A522T [98] T77I [98] V114A [98] P616L [98] | Amino acid substitutions that cause hypocholesterolaemia |
Ala68fsLeu82X [98] | Single nucleotide deletion in exon 1 that leads to a frameshift mutation that in turn causes the PCSK9 peptide to be shortened and not functional |
C679X (rs28362286) [122,123,124,125] Y142X (rs67608943) [124] | SNPs that lead to disruption in the folding of the protein and lower concentrations of Lp(a), LDLC, oxidised phospholipid (OxPL-ApoB), fasting glucose and glycated haemoglobin |
G106R [126] | GG/AG genotype in exon 2 that leads to a mutation in the prodomain due to which PCSK9 fails to undergo autocatalytic cleavage and causes an increase in the amount of surface LDLR |
G236S [119] Q152D [24] | PCSK9 fails to exit the ER due to abnormal folding of the protein causing hypocholesterolaemia |
N157K [126] | Causes hypocholesterolaemia, although studies do not exist on how the mutation causes the condition |
N354I [119] | PCSK9 fails to undergo autocatalytic cleavage leading to the production of inactive protein |
Arg46Leu [27,127] | Mutation in Exon 1 that leads to amino acid change of R46L and thereby to a lack of circulating PCSK9 |
Asp301Gly [27] | Mutation in Exon 6 that leads to amino acid change of D301G and thereby to a lack of circulating PCSK9 |
PCSK9-679X [97] | Elimination of final cysteine in the C-terminal domain that leads to PCSK9 failing to exit the ER after the protein folding is disrupted |
PCSK9-FS [24] | C-terminal frameshift by which PCSK9 fails to exit the ER |
Q152H (Gln152His) [24,128,129] | Amino acid substitution that prevents the autocatalytic processing of proPCSK9 inducing the reduction in circulating levels of PCSK9 and LDL-C, reduction in risk of developing CVD |
R434W [103] | Alteration in the hinge region that impedes PCSK9 retention in the Trans-Golgi network that causes lower secretion levels of PCSK9 |
rs11206510 [130,131,132] rs11583680 (A53V) [133] rs2479409 [134] rs151193009 (R93C) [100,134] | SNPs which lead to reduced risk of CAD, peripheral artery disease, abdominal aortic aneurysm, type 2 diabetes, ischemic stroke, dementia, chronic obstructive pulmonary artery disease and cancer |
rs11591147 (R46L) [126] | GT/TT genotype in exon 1 that leads to decreased levels of LDL-C and reduced risk of CVDs |
S127R [118] | Mutation in pro-domain that causes low binding affinity to LDLR and increased catabolism of LDLC |
S386A [126] R237W [126] | Point mutations in the catalytic domain that lead to the failure of PCSK9 to undergo autocatalytic cleavage |
Name of Mutation + Reference | Cause and Consequences |
---|---|
Arg499His [135] Arg496Trp [136] Asp129Gly [23] | Variations in C-terminal domain that drive the intracellular degradation of LDLR |
Asp374His [23] E32K (Leu108Arg) [23] D374H [137,138] | Causes increased binding affinity to LDLR and hypercholesterolaemia |
Asp374Tyr [103,136] | Mutation in the catalytic domain that improves the interaction of PCSK9 with the EGF-A domain of LDLR |
Asp35Tyr [23] | Mutation that creates a novel Tyr-sulfation site to enhance the intracellular activity of PCSK9 |
D129G [103] | Mutation in pro-domain that leads to faster protein mobility from ER to Golgi faster in comparison to normal PCSK9 |
D374Y (rs137852912) [103,104,126,137,139,140] R496W (rs374603772) [104] | Causes 10–25-fold higher binding capacity to LDLR causing early CAD, atherosclerosis |
D377Y [19] | Causes abdominal aortic aneurysm |
Phe216Leu [99] | Decreases the circulating LDLR levels due to its destruction with the help of PCSK9 intracellularly |
R215H [119] F216L [137,141] R218S [105] | SNPs that abolish furin cleavage |
R357H [142] | Mutation in catalytic domain that leads to hypercholesterolaemia |
R496Q [126] | Leads to hyperlipoproteinaemia |
S386A [141] F216L [104,137,141] | Increases secretion of ApoB100-containing lipoproteins |
S127R (rs28942111) [103,104,115,118,137,143,144] | Mutation in pro-domain that leads to increased binding affinity of PCSK9 to VLDLR and high circulating levels of VLDL, IDL and ApoB100-containing lipoproteins |
Ser127Arg [136] | Variation in pro-domain that improves the chance of preventing LDLR from entering a closed conformation |
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Sundararaman, S.S.; Döring, Y.; van der Vorst, E.P.C. PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology. Biomedicines 2021, 9, 793. https://doi.org/10.3390/biomedicines9070793
Sundararaman SS, Döring Y, van der Vorst EPC. PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology. Biomedicines. 2021; 9(7):793. https://doi.org/10.3390/biomedicines9070793
Chicago/Turabian StyleSundararaman, Sai Sahana, Yvonne Döring, and Emiel P. C. van der Vorst. 2021. "PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology" Biomedicines 9, no. 7: 793. https://doi.org/10.3390/biomedicines9070793