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Updated: Aug 6, 2026

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
08:14

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9

Published on: August 28, 2018

The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural

Suzanne Benjannet1, David Rhainds, Josée Hamelin

  • 1Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada.

The Journal of Biological Chemistry
|August 17, 2006
PubMed

Insights

Proprotein convertase subtilisin/kexin type 9 (PCSK9) mutations affect familial hypercholesterolemia. Furin and PC5/6A cleavage of PCSK9 regulates its levels and low-density lipoprotein (LDL) receptor degradation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) cholesterol metabolism.
  • Mutations in PCSK9 are linked to familial hypercholesterolemia and hypocholesterolemia.
  • PCSK9 enhances LDL receptor degradation, increasing circulating LDL levels.

Purpose of the Study:

  • To investigate the post-translational modifications and proteolytic processing of PCSK9.
  • To elucidate the functional impact of PCSK9 mutations on its processing and localization.
  • To understand the role of other proprotein convertases (PCs) in PCSK9 regulation.

Main Methods:

  • Analysis of PCSK9 post-translational modifications, including sulfation.
  • Assessment of PCSK9 susceptibility to cleavage by other PC family members.
  • Investigation of PCSK9 localization and processing in response to specific mutations.
  • Detection of PCSK9 forms in human plasma.

Main Results:

  • PCSK9 undergoes sulfation at Tyr38 within its prosegment.
  • Gain-of-function mutations (R218S, F216L, D374Y) impair furin/PC5/6A processing, associated with hypercholesterolemia.
  • Loss-of-function mutations (A443T, C679X) affect PCSK9 localization and processing, impacting LDL receptor interaction.
  • Both native and cleaved PCSK9 forms are detected in human plasma.

Conclusions:

  • PCSK9 levels are finely regulated by furin and PC5/6A cleavage.
  • This processing by furin and PC5/6A may reduce PCSK9's lifetime and LDL receptor degradation.
  • PCSK9 processing influences circulating LDL cholesterol levels, offering therapeutic insights.

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