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Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted protein that binds and mediates endo-lysosomal degradation of low-density lipoprotein receptor (LDLR), limiting plasma clearance of cholesterol-rich LDL particles in liver. Gain-of-function (GOF) point mutations in PCSK9 are associa...

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Autores principales: Sarkar, Samantha K., Matyas, Angela, Asikhia, Ikhuosho, Hu, Zhenkun, Golder, Mia, Beehler, Kaitlyn, Kosenko, Tanja, Lagace, Thomas A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9515655/
https://www.ncbi.nlm.nih.gov/pubmed/36187800
http://dx.doi.org/10.3389/fphys.2022.960272
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author Sarkar, Samantha K.
Matyas, Angela
Asikhia, Ikhuosho
Hu, Zhenkun
Golder, Mia
Beehler, Kaitlyn
Kosenko, Tanja
Lagace, Thomas A.
author_facet Sarkar, Samantha K.
Matyas, Angela
Asikhia, Ikhuosho
Hu, Zhenkun
Golder, Mia
Beehler, Kaitlyn
Kosenko, Tanja
Lagace, Thomas A.
author_sort Sarkar, Samantha K.
collection PubMed
description Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted protein that binds and mediates endo-lysosomal degradation of low-density lipoprotein receptor (LDLR), limiting plasma clearance of cholesterol-rich LDL particles in liver. Gain-of-function (GOF) point mutations in PCSK9 are associated with familial hypercholesterolemia (FH). Approximately 30%–40% of PCSK9 in normolipidemic human plasma is bound to LDL particles. We previously reported that an R496W GOF mutation in a region of PCSK9 known as cysteine-histidine–rich domain module 1 (CM1) prevents LDL binding in vitro [Sarkar et al., J. Biol. Chem. 295 (8), 2285–2298 (2020)]. Herein, we identify additional GOF mutations that inhibit LDL association, localized either within CM1 or a surface-exposed region in the PCSK9 prodomain. Notably, LDL binding was nearly abolished by a prodomain S127R GOF mutation, one of the first PCSK9 mutations identified in FH patients. PCSK9 containing alanine or proline substitutions at amino acid position 127 were also defective for LDL binding. LDL inhibited cell surface LDLR binding and degradation induced by exogenous PCSK9-D374Y but had no effect on an S127R-D374Y double mutant form of PCSK9. These studies reveal that multiple FH-associated GOF mutations in two distinct regions of PCSK9 inhibit LDL binding, and that the Ser-127 residue in PCSK9 plays a critical role.
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spelling pubmed-95156552022-09-29 Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding Sarkar, Samantha K. Matyas, Angela Asikhia, Ikhuosho Hu, Zhenkun Golder, Mia Beehler, Kaitlyn Kosenko, Tanja Lagace, Thomas A. Front Physiol Physiology Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted protein that binds and mediates endo-lysosomal degradation of low-density lipoprotein receptor (LDLR), limiting plasma clearance of cholesterol-rich LDL particles in liver. Gain-of-function (GOF) point mutations in PCSK9 are associated with familial hypercholesterolemia (FH). Approximately 30%–40% of PCSK9 in normolipidemic human plasma is bound to LDL particles. We previously reported that an R496W GOF mutation in a region of PCSK9 known as cysteine-histidine–rich domain module 1 (CM1) prevents LDL binding in vitro [Sarkar et al., J. Biol. Chem. 295 (8), 2285–2298 (2020)]. Herein, we identify additional GOF mutations that inhibit LDL association, localized either within CM1 or a surface-exposed region in the PCSK9 prodomain. Notably, LDL binding was nearly abolished by a prodomain S127R GOF mutation, one of the first PCSK9 mutations identified in FH patients. PCSK9 containing alanine or proline substitutions at amino acid position 127 were also defective for LDL binding. LDL inhibited cell surface LDLR binding and degradation induced by exogenous PCSK9-D374Y but had no effect on an S127R-D374Y double mutant form of PCSK9. These studies reveal that multiple FH-associated GOF mutations in two distinct regions of PCSK9 inhibit LDL binding, and that the Ser-127 residue in PCSK9 plays a critical role. Frontiers Media S.A. 2022-09-14 /pmc/articles/PMC9515655/ /pubmed/36187800 http://dx.doi.org/10.3389/fphys.2022.960272 Text en Copyright © 2022 Sarkar, Matyas, Asikhia, Hu, Golder, Beehler, Kosenko and Lagace. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Sarkar, Samantha K.
Matyas, Angela
Asikhia, Ikhuosho
Hu, Zhenkun
Golder, Mia
Beehler, Kaitlyn
Kosenko, Tanja
Lagace, Thomas A.
Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding
title Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding
title_full Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding
title_fullStr Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding
title_full_unstemmed Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding
title_short Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding
title_sort pathogenic gain-of-function mutations in the prodomain and c-terminal domain of pcsk9 inhibit ldl binding
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9515655/
https://www.ncbi.nlm.nih.gov/pubmed/36187800
http://dx.doi.org/10.3389/fphys.2022.960272
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