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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

LDLR-mediated LDL uptake.A: LDL binds to the LDLR on the cell surface, enters into cells via clathrin-dependent endocytosis, and delivered to endosomes[62]. B: The conformation of the LDLR is changed to a close conformation in the low pH environment of the endosome, which promotes the release of the bound LDL[10]. C: Released LDL is delivered to lysosomes for degradation. D: The LDLR is recycled to the cell surface.
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f01: LDLR-mediated LDL uptake.A: LDL binds to the LDLR on the cell surface, enters into cells via clathrin-dependent endocytosis, and delivered to endosomes[62]. B: The conformation of the LDLR is changed to a close conformation in the low pH environment of the endosome, which promotes the release of the bound LDL[10]. C: Released LDL is delivered to lysosomes for degradation. D: The LDLR is recycled to the cell surface.

Mentions: The LDLR in the liver is the protein primarily responsible for removal of LDL from the circulation[2,3]. The LDLR consists of 7 ligand-binding repeats (LR1-7) at the N terminus followed by the so-called epidermal growth factor (EGF) precursor homology domain (Fig. 1). The clustered O-linked sugar region (a threonine- and serine-rich region) is followed by the transmembrane domain and a relatively short cytoplasmic tail that are located downstream of the EGF precursor homology domain. Each LR consists of 7 individual 40-amino acid cysteine-rich tandem repeats. LR3 to LR7 are important for the binding of apolipoprotein B-100 on the surface of LDL, while LR4 and LR5 are important for binding to apolipoprotein E on VLDL surface[6]. The EGF precursor domain contains two cysteine-rich EGF-like domains (EGF-A and EGF-B) followed by a β-propeller domain/YWTD repeats and a third EGF-like domain (EGF-C)[7]. These EGF and YWTD repeats are required for lipoprotein release from the receptor in the endosome and recycling of the LDLR to the cell surface[8,9]. The cytoplasmic tail of LDLR contains all the sequences required for receptor clustering in clathrin-coated pits and for internalization of the receptor[8]. The crystallographic structure of the extracellular domain of the LDLR suggests that the extracellular domain of the cell-surface LDLR (neutral pH) adopts an extended linear conformation (open conformation) that favors interactions between the ligand binding repeats and LDL[10]. Upon ligand binding, the receptors are internalized via clathrin-coated pits and delivered to endosomes[2-3]. In the low pH environment of the endosome, the LDLR undergoes a conformational change so that LR4 and LR5 form a physical interaction with YWTD in the EGF precursor homology domain (closed conformation, Fig. 1B)[10]. The acid-dependent conformational change in the LDLR promotes the release of the bound LDL that is delivered to lysosomes for degradation (Fig. 1C) and signals recycling of the LDLR to the cell surface (Fig. 1D). Usually, each LDLR undergoes multiple rounds of internalization and recycling.


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

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

LDLR-mediated LDL uptake.A: LDL binds to the LDLR on the cell surface, enters into cells via clathrin-dependent endocytosis, and delivered to endosomes[62]. B: The conformation of the LDLR is changed to a close conformation in the low pH environment of the endosome, which promotes the release of the bound LDL[10]. C: Released LDL is delivered to lysosomes for degradation. D: The LDLR is recycled to the cell surface.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4585429&req=5

f01: LDLR-mediated LDL uptake.A: LDL binds to the LDLR on the cell surface, enters into cells via clathrin-dependent endocytosis, and delivered to endosomes[62]. B: The conformation of the LDLR is changed to a close conformation in the low pH environment of the endosome, which promotes the release of the bound LDL[10]. C: Released LDL is delivered to lysosomes for degradation. D: The LDLR is recycled to the cell surface.
Mentions: The LDLR in the liver is the protein primarily responsible for removal of LDL from the circulation[2,3]. The LDLR consists of 7 ligand-binding repeats (LR1-7) at the N terminus followed by the so-called epidermal growth factor (EGF) precursor homology domain (Fig. 1). The clustered O-linked sugar region (a threonine- and serine-rich region) is followed by the transmembrane domain and a relatively short cytoplasmic tail that are located downstream of the EGF precursor homology domain. Each LR consists of 7 individual 40-amino acid cysteine-rich tandem repeats. LR3 to LR7 are important for the binding of apolipoprotein B-100 on the surface of LDL, while LR4 and LR5 are important for binding to apolipoprotein E on VLDL surface[6]. The EGF precursor domain contains two cysteine-rich EGF-like domains (EGF-A and EGF-B) followed by a β-propeller domain/YWTD repeats and a third EGF-like domain (EGF-C)[7]. These EGF and YWTD repeats are required for lipoprotein release from the receptor in the endosome and recycling of the LDLR to the cell surface[8,9]. The cytoplasmic tail of LDLR contains all the sequences required for receptor clustering in clathrin-coated pits and for internalization of the receptor[8]. The crystallographic structure of the extracellular domain of the LDLR suggests that the extracellular domain of the cell-surface LDLR (neutral pH) adopts an extended linear conformation (open conformation) that favors interactions between the ligand binding repeats and LDL[10]. Upon ligand binding, the receptors are internalized via clathrin-coated pits and delivered to endosomes[2-3]. In the low pH environment of the endosome, the LDLR undergoes a conformational change so that LR4 and LR5 form a physical interaction with YWTD in the EGF precursor homology domain (closed conformation, Fig. 1B)[10]. The acid-dependent conformational change in the LDLR promotes the release of the bound LDL that is delivered to lysosomes for degradation (Fig. 1C) and signals recycling of the LDLR to the cell surface (Fig. 1D). Usually, each LDLR undergoes multiple rounds of internalization and recycling.

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