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Hypercholesterolemia, low density lipoprotein receptor and proprotein convertase subtilisin/kexin-type 9.

Gu HM, Zhang DW - J Biomed Res (2015)

Bottom Line: Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world.Mutations in the LDLR cause familiar hypercholesterolemia and increase the risk of premature coronary heart disease.In this review, we summarize the latest advances in the studies of PCSK9.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pediatrics and Biochemistry, Group on the Molecular and Cell Biology of Lipids, University of Alberta , Edmonton, Alberta, T6G 2S2 , Canada .

ABSTRACT
Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world. Plasma levels of low density lipoprotein cholesterol (LDL-C) are positively correlated with the risk of atherosclerosis. High plasma LDL concentrations in patients with hypercholesterolemia lead to build-up of LDL in the inner walls of the arteries, which becomes oxidized and promotes the formation of foam cells, consequently initiating atherosclerosis. Plasma LDL is mainly cleared through the LDL receptor (LDLR) pathway. Mutations in the LDLR cause familiar hypercholesterolemia and increase the risk of premature coronary heart disease. The expression of LDLR is regulated at the transcriptional level via the sterol regulatory element binding protein 2 (SREBP-2) and at the posttranslational levels mainly through proprotein convertase subtilisin/kexin-type 9 (PCSK9) and inducible degrader of the LDLR (IDOL). In this review, we summarize the latest advances in the studies of PCSK9.

No MeSH data available.


Related in: MedlinePlus

PCSK9 secretion and PCSK9-promoted LDLR degradation.PCSK9 contains a signal sequence followed by a prodomain, a catalytic domain, and a cysteine- and histidine-rich C-terminal domain. PCSK9 secretion: A: The protein is synthesized as a zymogen in the ER and then undergoes autocatalytic cleavage between the prodomain and the catalytic domain. The cleaved prodomain is tightly associated with the catalytic domain. B: PCSK9 is transported to the Golgi, where post-translational modifications, such as glycosylation and sulfation, occur. C: Mature PCSK9 is secreted from the cells. PCSK9-promoted LDLR degradation: (1) The catalytic domain and prodomain of PCSK9 bind to EGF-A and YWTD repeats of the LDLR, respectively. (2) PCSK9-LDLR complex enters into cells via clathrin-dependent endocytosis and is delivered to the endosome. (3) PCSK9 strongly binds to the LDLR at the acidic endosomal environment, which blocks recycling of the LDLR to the cell surface. (4) PCSK9-LDLR complex is transported to the lysosome for degradation.
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f02: PCSK9 secretion and PCSK9-promoted LDLR degradation.PCSK9 contains a signal sequence followed by a prodomain, a catalytic domain, and a cysteine- and histidine-rich C-terminal domain. PCSK9 secretion: A: The protein is synthesized as a zymogen in the ER and then undergoes autocatalytic cleavage between the prodomain and the catalytic domain. The cleaved prodomain is tightly associated with the catalytic domain. B: PCSK9 is transported to the Golgi, where post-translational modifications, such as glycosylation and sulfation, occur. C: Mature PCSK9 is secreted from the cells. PCSK9-promoted LDLR degradation: (1) The catalytic domain and prodomain of PCSK9 bind to EGF-A and YWTD repeats of the LDLR, respectively. (2) PCSK9-LDLR complex enters into cells via clathrin-dependent endocytosis and is delivered to the endosome. (3) PCSK9 strongly binds to the LDLR at the acidic endosomal environment, which blocks recycling of the LDLR to the cell surface. (4) PCSK9-LDLR complex is transported to the lysosome for degradation.

Mentions: PCSK9 is a member of the subtilisin-like serine protease family that includes 7 basic amino acid-specific proprotein convertases (PC): PC1, PC2, furin, PC4, PC5/6, PACE4, and PC7, as well as two members, site-1 protease and PCSK9, that cleave at the carboxyl terminus of non-basic residues[27]. PCSK9 is a 692-amino acid secreted glycoprotein that consists of a signal sequence followed by a prodomain, a catalytic domain, and a cysteine- and histidine-rich C-terminal domain (Fig. 2). PCSK9 is synthesized as a zymogen and undergoes autocatalytic cleavage in the endoplasmic reticulum (ER) at the FAQ152SIPK site (Fig. 2A). The autocatalytic cleavage is required for protein maturation and secretion[28]. The cleaved N-terminal prodomain is tightly associated with the rest of the catalytic C-terminus and secreted together from cells, physically shielding the catalytic activity as the protein transits through the secretory pathway[27]. Sec24A is required for the transport of PCSK9 from the ER to the Golgi, while sortilin interacts with PCSK9 in the trans-Golgi network and then facilitates its secretion[29]. The expression of PCSK9 is high in the liver, intestine, kidney, and brain[30] and regulated by the SREBP2 pathway[31]. PCSK9 is present in human plasma[15,32-34], and circulating levels of PCSK9 correlate with plasma levels of LDL-C but not HDL-C[33-34]. Overexpression of recombinant PCSK9 in the liver of mice causes a significant reduction in hepatic LDLR protein levels without any effect on its mRNA levels and produces severe hypercholesterolemia[28,35-36]. On the other hand, knockdown or knockout of PCSK9 expression in mice leads to increased levels of LDLR protein in the liver and accelerated LDL clearance[37-38]. The natural gain-of-function mutation, D374Y, has a significantly increased binding affinity for the LDLR and promotes LDLR degradation much more efficiently than the wild type protein[15,39], leading to a severe form of hypercholesterolemia[18]. FH mutation, LDLR-H306Y, binds PCSK9 with a higher affinity and exhibits enhanced sensitivity to PCSK9[40]. Taken together, these findings demonstrate that the role of PCSK9 in homeostatic control of plasma LDL-C levels is dependent upon PCSK9-promoted degradation of the LDLR, thereby preventing clearance of LDL-C by the cells[15-16,28,35-37,41-44].


Hypercholesterolemia, low density lipoprotein receptor and proprotein convertase subtilisin/kexin-type 9.

Gu HM, Zhang DW - J Biomed Res (2015)

PCSK9 secretion and PCSK9-promoted LDLR degradation.PCSK9 contains a signal sequence followed by a prodomain, a catalytic domain, and a cysteine- and histidine-rich C-terminal domain. PCSK9 secretion: A: The protein is synthesized as a zymogen in the ER and then undergoes autocatalytic cleavage between the prodomain and the catalytic domain. The cleaved prodomain is tightly associated with the catalytic domain. B: PCSK9 is transported to the Golgi, where post-translational modifications, such as glycosylation and sulfation, occur. C: Mature PCSK9 is secreted from the cells. PCSK9-promoted LDLR degradation: (1) The catalytic domain and prodomain of PCSK9 bind to EGF-A and YWTD repeats of the LDLR, respectively. (2) PCSK9-LDLR complex enters into cells via clathrin-dependent endocytosis and is delivered to the endosome. (3) PCSK9 strongly binds to the LDLR at the acidic endosomal environment, which blocks recycling of the LDLR to the cell surface. (4) PCSK9-LDLR complex is transported to the lysosome for degradation.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4585429&req=5

f02: PCSK9 secretion and PCSK9-promoted LDLR degradation.PCSK9 contains a signal sequence followed by a prodomain, a catalytic domain, and a cysteine- and histidine-rich C-terminal domain. PCSK9 secretion: A: The protein is synthesized as a zymogen in the ER and then undergoes autocatalytic cleavage between the prodomain and the catalytic domain. The cleaved prodomain is tightly associated with the catalytic domain. B: PCSK9 is transported to the Golgi, where post-translational modifications, such as glycosylation and sulfation, occur. C: Mature PCSK9 is secreted from the cells. PCSK9-promoted LDLR degradation: (1) The catalytic domain and prodomain of PCSK9 bind to EGF-A and YWTD repeats of the LDLR, respectively. (2) PCSK9-LDLR complex enters into cells via clathrin-dependent endocytosis and is delivered to the endosome. (3) PCSK9 strongly binds to the LDLR at the acidic endosomal environment, which blocks recycling of the LDLR to the cell surface. (4) PCSK9-LDLR complex is transported to the lysosome for degradation.
Mentions: PCSK9 is a member of the subtilisin-like serine protease family that includes 7 basic amino acid-specific proprotein convertases (PC): PC1, PC2, furin, PC4, PC5/6, PACE4, and PC7, as well as two members, site-1 protease and PCSK9, that cleave at the carboxyl terminus of non-basic residues[27]. PCSK9 is a 692-amino acid secreted glycoprotein that consists of a signal sequence followed by a prodomain, a catalytic domain, and a cysteine- and histidine-rich C-terminal domain (Fig. 2). PCSK9 is synthesized as a zymogen and undergoes autocatalytic cleavage in the endoplasmic reticulum (ER) at the FAQ152SIPK site (Fig. 2A). The autocatalytic cleavage is required for protein maturation and secretion[28]. The cleaved N-terminal prodomain is tightly associated with the rest of the catalytic C-terminus and secreted together from cells, physically shielding the catalytic activity as the protein transits through the secretory pathway[27]. Sec24A is required for the transport of PCSK9 from the ER to the Golgi, while sortilin interacts with PCSK9 in the trans-Golgi network and then facilitates its secretion[29]. The expression of PCSK9 is high in the liver, intestine, kidney, and brain[30] and regulated by the SREBP2 pathway[31]. PCSK9 is present in human plasma[15,32-34], and circulating levels of PCSK9 correlate with plasma levels of LDL-C but not HDL-C[33-34]. Overexpression of recombinant PCSK9 in the liver of mice causes a significant reduction in hepatic LDLR protein levels without any effect on its mRNA levels and produces severe hypercholesterolemia[28,35-36]. On the other hand, knockdown or knockout of PCSK9 expression in mice leads to increased levels of LDLR protein in the liver and accelerated LDL clearance[37-38]. The natural gain-of-function mutation, D374Y, has a significantly increased binding affinity for the LDLR and promotes LDLR degradation much more efficiently than the wild type protein[15,39], leading to a severe form of hypercholesterolemia[18]. FH mutation, LDLR-H306Y, binds PCSK9 with a higher affinity and exhibits enhanced sensitivity to PCSK9[40]. Taken together, these findings demonstrate that the role of PCSK9 in homeostatic control of plasma LDL-C levels is dependent upon PCSK9-promoted degradation of the LDLR, thereby preventing clearance of LDL-C by the cells[15-16,28,35-37,41-44].

Bottom Line: Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world.Mutations in the LDLR cause familiar hypercholesterolemia and increase the risk of premature coronary heart disease.In this review, we summarize the latest advances in the studies of PCSK9.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pediatrics and Biochemistry, Group on the Molecular and Cell Biology of Lipids, University of Alberta , Edmonton, Alberta, T6G 2S2 , Canada .

ABSTRACT
Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world. Plasma levels of low density lipoprotein cholesterol (LDL-C) are positively correlated with the risk of atherosclerosis. High plasma LDL concentrations in patients with hypercholesterolemia lead to build-up of LDL in the inner walls of the arteries, which becomes oxidized and promotes the formation of foam cells, consequently initiating atherosclerosis. Plasma LDL is mainly cleared through the LDL receptor (LDLR) pathway. Mutations in the LDLR cause familiar hypercholesterolemia and increase the risk of premature coronary heart disease. The expression of LDLR is regulated at the transcriptional level via the sterol regulatory element binding protein 2 (SREBP-2) and at the posttranslational levels mainly through proprotein convertase subtilisin/kexin-type 9 (PCSK9) and inducible degrader of the LDLR (IDOL). In this review, we summarize the latest advances in the studies of PCSK9.

No MeSH data available.


Related in: MedlinePlus