The Crystal Structure of PCSK9: A Regulator of Plasma LDL-Cholesterol

Piper, Derek E.; Jackson, Simon; Liu, Qiang; Romanow, William G.; Shetterly, Susan; Thibault, Stephen T.; Shan, Bei; Walker, Nigel

doi:10.1016/j.str.2007.04.004

Cited by 218 publications

(220 citation statements)

References 35 publications

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“…The C-terminal end of the prodomain is occluding the catalytic site (black circle). B. Clustered histidines (labeled) lie on one face of the C-terminal domain, suggesting a potential role in enhancing the affinity of PCSK9 for the LDLR at endosomal pH [29,31].…”

Section: Discussionmentioning

confidence: 99%

“…The structure of PCSK9 at neutral pH has now been reported by two groups, and raises many intriguing new questions about PCSK9 biochemistry and function [29,31]. The two most striking features of the structure are (i) the catalytic site of the enzyme is blocked by the prodomain in a non-covalent complex ( Figure 5A), and (ii) the C-terminal domain, which consists of three beta-domain modules related to one another by a pseudo three-fold axis, displays a surface rich in histidine residues along a stripe derived primarily from the second module ( Figure 5B).…”

Section: Pcsk9 Structurementioning

confidence: 95%

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Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers

Blacklow

2007

Current Opinion in Structural Biology

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SummaryProteins of the low-density lipoprotein receptor family transport cholesterol-carrying particles into cells, clear protease-inhibitor complexes from the circulation, participate in biological signaling cascades, and even serve as viral receptors. These receptors utilize clusters of cysteine-rich LDL receptor type-A (LA) modules to bind many of their ligands. Recent structures show that these modules typically exhibit a characteristic binding mode to recognize their partners, relying primarily on electrostatic complementarity and avidity effects. The dominant contribution of electrostatic interactions with small interface areas in these complexes allows binding to be regulated by changes in pH via at least two distinct mechanisms. The structure of the subtilisin/kexin family protease PCSK9, a newly identified molecular partner of the LDLR also implicated in LDL-cholesterol homeostasis, also raises the possibility that the LDLR and its related family members may employ other strategies for pH-sensitive binding that have yet to be uncovered.

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Section: Discussionmentioning

confidence: 99%

Section: Pcsk9 Structurementioning

confidence: 95%

Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers

Blacklow

2007

Current Opinion in Structural Biology

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“…The crystal structure study of a full-length construct of PCSK9 established that it binds to the extracellular domain of the LDL receptor [Cunningham et al, 2007;Piper et al, 2007]. The binding site for the LDLR EGF-A domain resides on the surface of PCSK9 that is formed primarily by residues 367 to 381.…”

Section: Impact Of Pcsk9 On the Ldl Receptormentioning

confidence: 99%

“…Finally, the low plasma LDL-C levels and the reduction of CHD displayed in PCSK9 loss-of-function mutation carriers, which seem furthermore healthy, indicate that the inhibition of PCSK9 should be an effective target in the treatment of hypercholesterolemia with no known adverse side effects. The recent elucidation of the crystal structure of PCSK9 [Cunningham et al, 2007;Piper et al, 2007], especially in complex with the LDL receptor [Kwon et al, 2008], should provide essential clues for the identification of small pharmacological molecules or antibodies that might block the interaction of PCSK9 and the LDLR and thus inhibit PCSK9 function and constitute new cholesterol-lowering drugs [Kwon et al, 2008;Grefhorst et al, 2008].…”

Section: Future Prospectsmentioning

confidence: 99%

Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

et al. 2009

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Hypercholesterolemia is one of the major causes of coronary heart disease (CHD). The genes encoding the low-density lipoprotein receptor and its ligand apolipoprotein B, have been the two genes classically implicated in autosomal dominant hypercholesterolemia (ADH). Our discovery in 2003 of the first mutations of the proprotein convertase subtilisin kexin 9 gene (PCSK9) causing ADH shed light on an unknown actor in cholesterol metabolism that since then has been extensively investigated. Several PCSK9 variants have been identified, some of them are gain-of-function mutations causing hypercholesterolemia by a reduction of low-density lipoprotein (LDL) receptor levels; while others are loss-of-function variants associated with a reduction of LDL-cholesterol (LDL-C) levels and a decreased risk of CHD. In this review, we focus on reported variants, and their biological, clinical, and functional relevance. We also highlight the spectrum of hypercholesterolemia or hypobetalipoproteinemia phenotypes that are already associated with mutations in PCSK9. Finally, we present future prospects concerning this therapeutic target that might constitute a new approach to reduce cholesterol levels and CHD, and enhance the effectiveness of other lipid-lowering drugs.

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“…4 Mature PCSK9 is secreted from the cell into circulation. [5][6][7][8] The circulating PCSK9 can bind to LDLR, leading to the co-internalization, followed by the degradation of LDLR. 9 Studies demonstrated that the overexpression of PCSK9 results in depletion of LDLR, and thus a dramatic increase in plasma level of cholesterol.…”

Section: Introductionmentioning

confidence: 99%

Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population

Alex¹,

Chahil²,

Lye³

et al. 2012

J Hum Genet

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Hypercholesterolemia is caused by different interactions of lifestyle and genetic determinants. At the genetic level, it can be attributed to the interactions of multiple polymorphisms, or as in the example of familial hypercholesterolemia (FH), it can be the result of a single mutation. A large number of genetic markers, mostly single nucleotide polymorphisms (SNP) or mutations in three genes, implicated in autosomal dominant hypercholesterolemia (ADH), viz APOB (apolipoprotein B), LDLR (low density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type-9), have been identified and characterized. However, such studies have been insufficiently undertaken specifically in Malaysia and Southeast Asia in general. The main objective of this study was to identify ADH variants, specifically ADH-causing mutations and hypercholesterolemia-associated polymorphisms in multiethnic Malaysian population. We aimed to evaluate published SNPs in ADH causing genes, in this population and to report any unusual trends. We examined a large number of selected SNPs from previous studies of APOB, LDLR, PCSK9 and other genes, in clinically diagnosed ADH patients (n ¼ 141) and healthy control subjects (n ¼ 111). Selection of SNPs was initiated by searching within genes reported to be associated with ADH from known databases. The important finding was 137 mono-allelic markers (44.1%) and 173 polymorphic markers (55.8%) in both subject groups.

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The Crystal Structure of PCSK9: A Regulator of Plasma LDL-Cholesterol

Cited by 218 publications

References 35 publications

Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers

Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers

Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population

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