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, Lene; Cameron, Jamie; Strøm, Thea Bismo; Leren, Trond P.

doi:10.1016/j.ymgmr.2016.11.003

Cited by 10 publications

(7 citation statements)

References 39 publications

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“…The prodomain sequence is rich in acidic residues and has been suggested to play an autoinhibitory role through interaction with the basic residues in the PCSK9 catalytic domain [ 14 ]. Another possible regulatory function of the acid prodomain sequence has been proposed as around 40% of PCSK9 in plasma is associated with LDL-C particles and in vitro prodomain truncation variant lacking residues 31–52 is unable to bind LDL-C [ 207 ]. Furthermore, in cell-based experiments LDL-C particles lower the LDLR degradation activity of PCSK9 [ 91 ].…”

Section: Introductionmentioning

confidence: 99%

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

et al. 2017

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Ischemic heart disease is the main cause of death worldwide and is accelerated by increased levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL-C through its ability to induce degradation of the LDL receptor (LDLR) in the lysosome of hepatocytes. Only in the last few years, a number of breakthroughs in the understanding of PCSK9 biology have been reported illustrating how PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Two humanized antibodies directed against the LDLR-binding site in PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics are climbing up the phases of clinical trials. The first outcome data of the PCSK9 inhibitor evolocumab reported a significant reduction in the composite endpoint (cardiovascular death, myocardial infarction, or stroke) and further outcome data are awaited. Meanwhile, it became evident that PCSK9 has (patho)physiological roles in several cardiovascular cells. In this review, we summarize and discuss the recent biological and clinical data on PCSK9, the regulation of PCSK9, its extra-hepatic activities focusing on cardiovascular cells, molecular concepts to target PCSK9, and finally briefly summarize the data of recent clinical studies.

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Section: Introductionmentioning

confidence: 99%

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

et al. 2017

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“…To more quantitatively assess the effect of the A44P mutation in full-length PCSK9, we performed a steady-state binding analysis in which fluorescent dye-labeled WT PCSK9 was incubated with LDL in the presence of increasing concentrations of unlabeled WT PCSK9 or PCSK9-A44P. For comparison purposes, we also included PCSK9 lacking the N-terminal 21 residues (⌬31-52), which is defective in LDL binding (18) and hyperactive in terms of LDLR binding/degradation (27,34). Competition binding curves showed that the PCSK9-A44P mutant had a Ͼ5-fold decrease in LDL binding affinity compared with WT PCSK9 (Fig.…”

Section: Helical Conformation Specifically Affects Pcsk9 Binding Affimentioning

confidence: 99%

A transient amphipathic helix in the prodomain of PCSK9 facilitates binding to low-density lipoprotein particles

Sarkar

Foo

Matyas

et al. 2020

Journal of Biological Chemistry

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Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a ligand of low-density lipoprotein (LDL) receptor (LDLR) that promotes LDLR degradation in late endosomes/lysosomes. In human plasma, 30–40% of PCSK9 is bound to LDL particles; however, the physiological significance of this interaction remains unknown. LDL binding in vitro requires a disordered N-terminal region in PCSK9's prodomain. Here, we report that peptides corresponding to a predicted amphipathic α-helix in the prodomain N terminus adopt helical structure in a membrane-mimetic environment. This effect was greatly enhanced by an R46L substitution representing an atheroprotective PCSK9 loss-of-function mutation. A helix-disrupting proline substitution within the putative α-helical motif in full-length PCSK9 lowered LDL binding affinity >5-fold. Modeling studies suggested that the transient α-helix aligns multiple polar residues to interact with positively charged residues in the C-terminal domain. Gain-of-function PCSK9 mutations associated with familial hypercholesterolemia (FH) and clustered at the predicted interdomain interface (R469W, R496W, and F515L) inhibited LDL binding, which was completely abolished in the case of the R496W variant. These findings shed light on allosteric conformational changes in PCSK9 required for high-affinity binding to LDL particles. Moreover, the initial identification of FH-associated mutations that diminish PCSK9's ability to bind LDL reported here supports the notion that PCSK9-LDL association in the circulation inhibits PCSK9 activity.

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“…PCSK9 is the ninth member of the protein convertase family that is synthesized as a proprotein and requires an autocatalytic cleavage to become mature [ 56 ]. The result of the cleave is a N-terminal prodomain that remains bound to the catalytic domain and inhibits convertase function [ 57 ].…”

Section: Cholesterol Metabolismmentioning

confidence: 99%

Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease

Benito‐Vicente

Uribe

Jebari

et al. 2018

IJMS

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Cholesterol is an essential component of cell barrier formation and signaling transduction involved in many essential physiologic processes. For this reason, cholesterol metabolism must be tightly controlled. Cell cholesterol is mainly acquired from two sources: Dietary cholesterol, which is absorbed in the intestine and, intracellularly synthesized cholesterol that is mainly synthesized in the liver. Once acquired, both are delivered to peripheral tissues in a lipoprotein dependent mechanism. Malfunctioning of cholesterol metabolism is caused by multiple hereditary diseases, including Familial Hypercholesterolemia, Sitosterolemia Type C and Niemann-Pick Type C1. Of these, familial hypercholesterolemia (FH) is a common inherited autosomal co-dominant disorder characterized by high plasma cholesterol levels. Its frequency is estimated to be 1:200 and, if untreated, increases the risk of premature cardiovascular disease. This review aims to summarize the current knowledge on cholesterol metabolism and the relation of FH to cholesterol homeostasis with special focus on the genetics, diagnosis and treatment.

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

Cited by 10 publications

References 39 publications

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

A transient amphipathic helix in the prodomain of PCSK9 facilitates binding to low-density lipoprotein particles

Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease

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