Removal of acidic residues of the prodomain of PCSK9 increases its activity towards the LDL receptor

Holla, Øystein L.; Laerdahl, Jon K.; Strøm, Thea Bismo; Tveten, Kristian; Cameron, Jamie; Leren, Trond P.

doi:10.1016/j.bbrc.2011.02.023

Cited by 26 publications

(27 citation statements)

References 20 publications

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“…Previous studies have shown that negatively charged residues of the unstructured part of the prodomain of PCSK9 (residues 31-60) have an inhibitory effect on the activity of PCSK9 ( 7,12,19 ). One may therefore speculate that the negatively charged unstructured part of the prodomain exerts its negative effect on the activity of PCSK9 by partly neutralizing an electrostatic attraction between the positively charged C-terminal domain of PCSK9 and negatively charged structures within the LDLR.…”

Section: Effect Of Replacing the C-terminal Domain With An Unrelated mentioning

confidence: 99%

“…HepG2 cells (European Collection of Cell Cultures, Wiltshire, UK) were cultured in modifi ed Eagle´s medium (Gibco, Carlsbad, CA) as previously described ( 12 ). For experiments, HepG2 cells were seeded out in collagen-coated 12-well plates (for fl ow cytometry) or 6-well plates (for Western blot analysis) (BD Biosciences, San Diego, CA) and transiently transfected with the different PCSK9-containing plasmids using Fugene HD (Roche Diagnostics GmbH, Mannheim, Germany) according to the manufacturer´s instructions.…”

Section: Cell Culturementioning

confidence: 99%

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Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors

Holla¹,

Cameron²,

Tveten³

et al. 2011

Journal of Lipid Research

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Section: Effect Of Replacing the C-terminal Domain With An Unrelated mentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors

Holla¹,

Cameron²,

Tveten³

et al. 2011

Journal of Lipid Research

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“…Mapping studies identified an N-terminal region of the PCSK9 prodomain (aa 31–52) as being required for LDL association in vitro [42 ▪▪ ]. This region appears to act as a negative allosteric effector of LDLR binding [8,43,44]. Thus, one possibility is that binding to LDL-apoB100 stabilizes a native autoinhibited conformation of PCSK9.…”

Section: Regulation Of Circulating Pcsk9 Activitymentioning

confidence: 99%

PCSK9 and LDLR degradation

Lagace

2014

Current Opinion in Lipidology

290

129

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Purpose of reviewProprotein convertase subtilisin/kexin type-9 (PCSK9) binds to LDL receptor (LDLR) and targets it for lysosomal degradation in cells. Decreased hepatic clearance of plasma LDL-cholesterol is the primary gauge of PCSK9 activity in humans; however, PCSK9's evolutionary role may extend to other lipoprotein classes and processes. This review highlights studies that are providing novel insights into physiological regulation of PCSK9 transcription and plasma PCSK9 activity.Recent findingsRecent studies indicate that circulating PCSK9 binds to apolipoprotein B100 on LDL particles, which in turn inhibits PCSK9's ability to bind to cell surface LDLRs. Negative feedback of secreted PCSK9 activity by LDL could serve to increase plasma excursion of triglyceride-rich lipoproteins and monitor lipoprotein remodeling. Recent findings have identified hepatocyte nuclear factor-1α as a key transcriptional regulator that cooperates with sterol regulatory element-binding protein-2 to control PCSK9 expression in hepatocytes in response to nutritional and hormonal inputs, as well as acute inflammation.SummaryPCSK9 is an established target for cholesterol-lowering therapies. Further study of PCSK9 regulatory mechanisms may identify additional control points for pharmacological inhibition of PCSK9-mediated LDLR degradation. PCSK9 function could reflect ancient roles in the fasting-feeding cycle and in linking lipoprotein metabolism with innate immunity.

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“…At the plasma membrane (i.e., at neutral pH), only the catalytic domain of PCSK9 interacts with the EGFA domain of the receptor ( 30,31,33 ). The acidic stretch located within the prodomain negatively modulates the binding affi nity between PCSK9 and the LDLR ( 34,35 ). In contrast, after endocytosis (i.e., at the acidic pH of endosomes), the affi nity between the receptor and PCSK9 is much higher (K d of 1-8 nM) than that observed at neutral pH ( 27,30,31 ).…”

Section: Pcsk9 Blocks the Structural Transition Of The Ldlr In The Enmentioning

confidence: 99%

The PCSK9 decade

Lambert

Sjouke

Choque

et al. 2012

Journal of Lipid Research

406

224

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Abbreviations: ARH, autosomal recessive hypercholesterolemia; ASO, antisense oligonucleotide; CAD, coronary artery disease; CVD, cardiovascular disease; EGFA, epidermal growth factor-like repeat homology domain; FH, familial hypercholesterolemia; HDL-C, highdensity lipoprotein cholesterol; HNF1a, hepatocyte nuclear factor 1a; LDL-C, low-density lipoprotein cholesterol; LDLR, LDL receptor; LNA, locked nucleic acid; LOD, logarithm of the odds; monoclonal antibody, MAb; PCSK9, proprotein convertase subtilisin kexin type 9; siRNA, small interfering RNA; SREBP2, sterol-responsive element-binding protein 2.

show abstract

Removal of acidic residues of the prodomain of PCSK9 increases its activity towards the LDL receptor

Cited by 26 publications

References 20 publications

Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors

Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors

PCSK9 and LDLR degradation

The PCSK9 decade

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