Cell-associated heparin-like molecules modulate the ability of LDL to regulate PCSK9 uptake

Galvan, Adri M.; Chorba, John S.

doi:10.1194/jlr.m087189

Cited by 17 publications

(18 citation statements)

References 64 publications

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“…PCSK9-LDL binding in vitro is saturable and specific with a K D of ϳ125-350 nM (18,21), which is within a range of affinities reported for the PCSK9-LDLR interaction (11,22). Several studies have shown that LDL lowers PCSK9's ability to bind and mediate degradation of LDLRs in cultured cells (18,22,23). Conversely, there is evidence that LDL association promotes PCSK9-mediated LDLR degradation by inducing a more potent oligomeric form (13,24) or by shielding PCSK9 from inactivating furin-mediated proteolysis (25).…”

supporting

confidence: 65%

“…Two such factors are known to improve the LDLRbinding function of PCSK9, namely acidic pH (11,16,22) and its association with heparin sulfate proteoglycans at the surface of hepatocytes (59). Heparin sulfate proteoglycans were recently shown to modulate the ability of LDL to inhibit PCSK9 activity, suggesting an interplay between these regulatory factors (23).…”

Section: Pcsk9 Mutations In Hypercholesterolemiamentioning

confidence: 99%

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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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supporting

confidence: 65%

Section: Pcsk9 Mutations In Hypercholesterolemiamentioning

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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show abstract

“…PCSK9-LDL binding in vitro is saturable and specific with a KD of ~125-350 nM (18,21), which is within a range of affinities reported for the PCSK9-LDLR interaction (11,22). Several studies have shown that LDL lowers PCSK9's ability to bind and mediate degradation of LDLRs in cultured cells (18,22,23). Conversely, there is evidence that LDL association promotes PCSK9-mediated LDLR degradation by inducing a more potent oligomeric form (13,24) or by shielding PCSK9 from inactivating furin-mediated proteolysis (25).…”

supporting

confidence: 63%

“…Two such factors are known to improve the LDLR binding function of PCSK9, namely acidic pH (11,16,22) and its association with heparin-sulfate proteoglycans (HSPGs) at the surface of hepatocytes (59). HSPGs were recently shown to modulate the ability of LDL to inhibit PCSK9 activity, suggesting an interplay between these regulatory factors (23).…”

Section: Discussionmentioning

confidence: 99%

A transient amphipathic helix in PCSK9’s prodomain facilitates low-density lipoprotein binding

Sarkar

Foo

Matyas

et al. 2019

Preprint

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Keywords: proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein (LDL), cholesterol regulation, intrinsically disordered protein, conformational change, computer modeling SUMMARYProprotein convertase subtilisin/kexin type-9 (PCSK9) is a ligand of low-density lipoprotein 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 ahelix in the prodomain N-terminus adopted 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 a-helical motif in full-length PCSK9 lowered LDL binding affinity >5-fold. Modeling studies suggested the transient a-helix aligns multiple polar residues to interact with positivecharged 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, F515L) inhibited LDL binding, which was abolished for the R496W variant. These studies inform on allosteric conformational changes in PCSK9 required for high-affinity binding to LDL particles. Moreover, we report the initial identification of FH-associated mutations that diminish the ability of PCSK9 to bind LDL, supporting that LDL association in the circulation inhibits PCSK9 activity. PCSK9 mutations in hypercholesterolemia

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“…In addition, incubation of HEK293 or HepG2 cells with PCSK9-S127R versus WT PCSK9 resulted in a lower LDL uptake, in accord with a GOF on the LDLR ( 77 ). The fact that mature PCSK9-S127R has an increased affinity for heparin-like coreceptor molecules and binds more strongly to the LDLR ( 74 ) also support a GOF phenotype ( 78 ). Altogether, the S127R variation may have multiple GOF consequences that ultimately lead to higher circulating LDL-C.…”

Section: Pcsk9 Protein Enhances the Degradation Of The Ldlr In Endosomes/lysosomesmentioning

confidence: 99%

The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer

Seidah

2021

Journal of Lipid Research

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Cell-associated heparin-like molecules modulate the ability of LDL to regulate PCSK9 uptake

Cited by 17 publications

References 64 publications

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

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

A transient amphipathic helix in PCSK9’s prodomain facilitates low-density lipoprotein binding

The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer

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