PCSK9 acts as a chaperone for the LDL receptor in the endoplasmic reticulum

Strøm, Thea Bismo; Tveten, Kristian; Leren, Trond P.

doi:10.1042/bj20130930

Cited by 43 publications

(35 citation statements)

References 34 publications

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“…PCSK9 enhances LDLR lysosomal degradation, resulting in reduced LDL-C clearance, thereby leading elevated serum LDL-C levels [22, 23]. Functional mutations of PCSK9 could have a real impact on serum lipids level and cardiovascular risk.…”

Section: Discussionmentioning

confidence: 99%

What is the impact of PCSK9 rs505151 and rs11591147 polymorphisms on serum lipids level and cardiovascular risk: a meta-analysis

Qiu

Zeng

et al. 2017

Lipids Health Dis

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Background PCSK9 rs505151 and rs11591147 polymorphisms are identified as gain- and loss-of-function mutations, respectively. The effects of these polymorphisms on serum lipid levels and cardiovascular risk remain to be elucidated.MethodsIn this meta-analysis, we explored the association of PCSK9 rs505151 and rs11591147 polymorphisms with serum lipid levels and cardiovascular risk by calculating the standardized mean difference (SMD) and odds ratios (OR) with 95% confidence intervals (CI).ResultsPooled results analyzed under a dominant genetic model indicated that the PCSK9 rs505151 G allele was related to higher levels of triglycerides (SMD: 0.14, 95% CI: 0.02 to 0.26, P = 0.021, I2 = 0) and low-density lipoproteins cholesterol (LDL-C) (SMD: 0.17, 95% CI: 0.00 to 0.35, P = 0.046, I2 = 75.9%) and increased cardiovascular risk (OR: 1.50, 95% CI: 1.19 to 1.89, P = 0.0006, I2 = 48%). The rs11591147 T allele was significantly associated with lower levels of total cholesterol (TC) and LDL-C (TC, SMD: -0.45, 95% CI: -0.57 to −0.32, P = 0.000, I2 = 0; LDL-C, SMD: -0.44, 95% CI: -0.55 to −0.33, P = 0.000, I2 = 0) and decreased cardiovascular risk (OR: 0.77, 95% CI: 0.60 to 0.98, P = 0.031, I2 = 59.9) in Caucasians.ConclusionsThis study indicates that the variant G allele of PCSK9 rs505151 confers increased triglyceride (TG) and LDL-C levels, as well as increased cardiovascular risk. Conversely, the variant T allele of rs11591147 protects carriers from cardiovascular disease susceptibility and lower TC and LDL-C levels in Caucasians. These findings provide useful information for researchers interested in the fields of PCSK9 genetics and cardiovascular risk prediction not only for designing future studies, but also for clinical and public health applications.

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Section: Discussionmentioning

confidence: 99%

What is the impact of PCSK9 rs505151 and rs11591147 polymorphisms on serum lipids level and cardiovascular risk: a meta-analysis

Qiu

Zeng

et al. 2017

Lipids Health Dis

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“…These findings lend support to the concept that PCSK9 secretion occurs in a highly regulated manner. A recent report has also suggested that the ectodomain of the LDL-R acts as a chaperone for PCSK9 folding and cleavage, increasing throughput from the proPCSK9 form to the cleaved mature form (41). Furthermore, mutations in the CHR domain, which do not affect self-proteolysis, have been noted to cause PCSK9 loss-of-function by interfering with the secretion pathway (42).…”

Section: Discussionmentioning

confidence: 99%

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Active Site and Cleavage Sequence Differentially Regulate Protein Secretion from Proteolysis

Chorba

Shokat

2014

Journal of Biological Chemistry

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Background: PCSK9 inhibition shows promise in the treatment of hypercholesterolemia and prevention of atherosclerotic heart disease. Results: PCSK9 proteolysis and secretion have different structural requirements near the protein active site. Conclusion: PCSK9 proteolysis and secretion occur in two separate steps. Significance: The PCSK9 active site can serve as an allosteric modulator of protein secretion, suggesting a new strategy for inhibition.

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“…It has previously been shown that binding of PCSK9 to the LDLR in the endoplasmic reticulum promotes autocatalytic cleavage of PCSK9 [27], [28]. Thus, reduced binding of PCSK9 to the LDLR in the presence of Pro31–52, could explain the inhibitory effect of this segment both on the autocatalytic cleavage and on the affinity to bind to the LDLR at the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Studies of the autoinhibitory segment comprising residues 31–60 of the prodomain of PCSK9: Possible implications for the mechanism underlying gain-of-function mutations

Wierød

Cameron

Strøm

et al. 2016

Molecular Genetics and Metabolism Reports

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) at the cell surface and is internalized as a complex with the LDLR. In the acidic milieu of the sorting endosome, PCSK9 remains bound to the LDLR and prevents the LDLR from folding over itself to adopt a closed conformation. As a consequence, the LDLR fails to recycle back to the cell membrane. Even though it is the catalytic domain of PCSK9 that interacts with the LDLR at the cell surface, the structurally disordered segment consisting of residues 31–60 and which is rich in acidic residues, has a negative effect both on autocatalytic cleavage and on the activity of PCSK9 towards the LDLR. Thus, this unstructured segment represents an autoinhibitory domain of PCSK9. One may speculate that post-translational modifications within residues 31–60 may affect the inhibitory activity of this segment, and represent a mechanism for fine-tuning the activity of PCSK9 towards the LDLR. Our data indicate that the inhibitory effect of this unstructured segment results from an interaction with basic residues of the catalytic domain of PCSK9. Mutations in the catalytic domain which involve charged residues, could therefore be gain-of-function mutations by affecting the positioning of this segment.

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PCSK9 acts as a chaperone for the LDL receptor in the endoplasmic reticulum

Cited by 43 publications

References 34 publications

What is the impact of PCSK9 rs505151 and rs11591147 polymorphisms on serum lipids level and cardiovascular risk: a meta-analysis

What is the impact of PCSK9 rs505151 and rs11591147 polymorphisms on serum lipids level and cardiovascular risk: a meta-analysis

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Active Site and Cleavage Sequence Differentially Regulate Protein Secretion from Proteolysis

Studies of the autoinhibitory segment comprising residues 31–60 of the prodomain of PCSK9: Possible implications for the mechanism underlying gain-of-function mutations

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