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

Journal of Lipid Research
Carlota OleagaSergio Fazio

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism by inducing the degradation of hepatic low-density lipoprotein receptor (LDLR). Plasma PCSK9 has two 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 LDLR. We aimed to identify the site of PCSK9_55 formation (intra- vs. extracellular) and to further characterize the LDLR-degradative function of PCSK9_55 relative to PCSK9_62. Co-expressing 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, 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 non-secreted PCSK9_55 was able to induce degradation of LDLR, though with 50% lower efficiency compared with PCSK9_62. Collectively, our data show that PCSK9_55 is generate...Continue Reading

References

Sep 15, 1993·Biochemical and Biophysical Research Communications·G VidricaireR Leduc
Feb 15, 2000·Methods : a Companion to Methods in Enzymology·J K VanSlyke, L S Musil
Sep 11, 2002·FEBS Letters·Jean DenaultRichard Leduc
Oct 3, 2002·Nature Reviews. Molecular Cell Biology·Gary Thomas
May 6, 2003·Nature Genetics·Marianne AbifadelCatherine Boileau
May 1, 2004·Proceedings of the National Academy of Sciences of the United States of America·Kara N Maxwell, Jan L Breslow
Jan 29, 2005·Proceedings of the National Academy of Sciences of the United States of America·Kara N MaxwellJan L Breslow
Mar 24, 2006·The New England Journal of Medicine·Jonathan C CohenHelen H Hobbs
Nov 3, 2006·The Journal of Clinical Investigation·Thomas A LagaceJay D Horton
Jun 1, 2007·The Journal of Biological Chemistry·Markey C McNuttJay D Horton
Jan 17, 2008·Biochemistry·Daping FanSergio Fazio
Nov 21, 2008·Journal of Lipid Research·Jay D HortonHelen H Hobbs
Oct 13, 2010·The Journal of Biological Chemistry·Suzanne BenjannetNabil G Seidah
Dec 15, 2010·The Journal of Biological Chemistry·Rachid EssalmaniAnnik Prat
Aug 28, 2013·Proceedings of the National Academy of Sciences of the United States of America·Prashant Nair
Apr 30, 2014·Journal of Lipid Research·Bomie HanKrista M Schroeder
Mar 17, 2015·The New England Journal of Medicine·Jennifer G RobinsonUNKNOWN ODYSSEY LONG TERM Investigators
Mar 17, 2015·The New England Journal of Medicine·Marc S SabatineUNKNOWN Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators
Sep 26, 2015·Biomedical Reports·Chikara UeyamaYoshiji Yamada
Oct 22, 2015·Biomarkers : Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals·Shadia A FathyAyman M Abu Mustafa
Apr 29, 2016·Circulation Research·Hagai TavoriSergio Fazio
Jun 22, 2017·The Journal of Clinical Endocrinology and Metabolism·Sergio FazioHagai Tavori
Mar 1, 2018·Molecular & Cellular Proteomics : MCP·Vagisha SharmaBrendan MacLean
May 12, 2018·Circulation Research·Michael D ShapiroSergio Fazio
Jan 18, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Gopala K YakalaRoshni R Singaraja
Mar 5, 2019·Journal of Visualized Experiments : JoVE·Nicholas McCaulIneke Braakman

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