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Oleaga C, Hay J, Gurcan E, et al. Insights into the kinetics and dynamics of the furin-cleaved form of PCSK9. J Lipid Res. 2020;62:100003doi: 10.1194/jlr.RA120000964.
Oleaga, C., Hay, J., Gurcan, E., David, L. L., Mueller, P. A., Tavori, H., Shapiro, M. D., Pamir, N., & Fazio, S. (2021). Insights into the kinetics and dynamics of the furin-cleaved form of PCSK9. Journal of lipid research, 62100003. https://doi.org/10.1194/jlr.RA120000964
Oleaga, Carlota, et al. "Insights into the kinetics and dynamics of the furin-cleaved form of PCSK9." Journal of lipid research vol. 62 (2021): 100003. doi: https://doi.org/10.1194/jlr.RA120000964
Oleaga C, Hay J, Gurcan E, David LL, Mueller PA, Tavori H, Shapiro MD, Pamir N, Fazio S. Insights into the kinetics and dynamics of the furin-cleaved form of PCSK9. J Lipid Res. 2021;62:100003. doi: 10.1194/jlr.RA120000964. Epub 2020 Nov 23. PMID: 33429337; PMCID: PMC7890205.
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J Lipid Res. 2021;62:100003. doi: 10.1194/jlr.RA120000964. Epub 2020 Nov 23.

Insights into the kinetics and dynamics of the furin-cleaved form of PCSK9.

Journal of lipid research

Carlota Oleaga, Joshua Hay, Emma Gurcan, Larry L David, Paul A Mueller, Hagai Tavori, Michael D Shapiro, Nathalie Pamir, Sergio Fazio

Affiliations

  1. Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health & Science University, Portland, OR, USA.
  2. Proteomics Shared Resource, Oregon Health & Science University, Portland, OR, USA.
  3. Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health & Science University, Portland, OR, USA. Electronic address: [email protected].

PMID: 33429337 PMCID: PMC7890205 DOI: 10.1194/jlr.RA120000964

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism by inducing the degradation of hepatic low density lipoprotein receptors (LDLRs). Plasma PCSK9 has 2 main molecular forms: a 62 kDa mature form (PCSK9_62) and a 55 kDa, furin-cleaved form (PCSK9_55). PCSK9_55 is considered less active than PCSK9_62 in degrading LDLRs. We aimed to identify the site of PCSK9_55 formation (intracellular vs. extracellular) and to further characterize the LDLR-degradative function of PCSK9_55 relative to PCSK9_62. Coexpressing PCSK9_62 with furin in cell culture induced formation of PCSK9_55, most of which was found in the extracellular space. Under the same conditions, we found that i) adding a cell-permeable furin inhibitor preferentially decreased the formation of PCSK9_55 extracellularly; ii) using pulse-chase analysis, we observed the formation of PCSK9_55 exclusively extracellularly in a time-dependent manner. A recombinant form of PCSK9_55 was efficiently produced but displayed impaired secretion that resulted in its intracellular trapping. However, the nonsecreted PCSK9_55 was able to induce degradation of LDLR, though with 50% lower efficiency than PCSK9_62. Collectively, our data show that 1) PCSK9_55 is formed extracellularly; 2) PCSK9_55 has a shorter half-life; 3) there is a small intracellular pool of PCSK9_55 that is not secreted; and 4) PCSK9_55 retained within the cell maintains a reduced efficiency to cause LDLR degradation.

Published by Elsevier Inc.

Keywords: LDL cholesterol; LDL receptor; PCSK9; cardiovascular disease; lipoprotein metabolism; posttranslational modifications; proprotein convertases

Conflict of interest statement

Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article

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