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• W2969533384 abstract "SUMMARY Proprotein 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 α-helix in the prodomain N-terminus adopted helical structure in a membrane-mimetic environment; this effect was greatly enhanced by an R46L substitution representing an athero-protective 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 the transient α-helix aligns multiple polar residues to interact with positive-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, 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." @default.
• W2969533384 created "2019-08-29" @default.
• W2969533384 creator A5008454570 @default.
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• W2969533384 creator A5066592019 @default.
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• W2969533384 creator A5088248473 @default.
• W2969533384 date "2019-08-22" @default.
• W2969533384 modified "2023-09-23" @default.
• W2969533384 title "A transient amphipathic helix in PCSK9’s prodomain facilitates low-density lipoprotein binding" @default.
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• W2969533384 doi "https://doi.org/10.1101/743195" @default.
• W2969533384 hasPublicationYear "2019" @default.
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• W2969533384 hasAuthorship W2969533384A5073712525 @default.
• W2969533384 hasAuthorship W2969533384A5088248473 @default.

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