Christian Brix Folsted Andersen

Heparan sulfate proteoglycans present PCSK9 to the LDL receptor

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  • Camilla Gustafsen
  • Ditte Olsen
  • ,
  • Joachim Vilstrup
  • ,
  • Signe Lund, MIND Center Department of Biomedicine, Ole Worms Allé 3, Aarhus University, 8000 Aarhus, Denmark.
  • ,
  • Anika Reinhardt, Scienion AG, Volmerstrasse 7b, 12489, Berlin, Germany.
  • ,
  • Niels Wellner
  • ,
  • Torben Larsen
  • Christian B F Andersen
  • Kathrin Weyer
  • Jin-Ping Li, Department of Medical Biochemistry and Microbiology, University of Uppsala, Husarg. 3, 75237, Uppsala, Sweden.
  • ,
  • Peter H Seeberger, Department of Biomolecular Systems, Max Planck Institute for Colloids and Interfaces, Am Mühlenberg 1 OT Golm, 14476, Potsdam, Germany.
  • ,
  • Søren Thirup
  • Peder Madsen
  • Simon Glerup

Coronary artery disease is the main cause of death worldwide and accelerated by increased plasma levels of cholesterol-rich low-density lipoprotein particles (LDL). Circulating PCSK9 contributes to coronary artery disease by inducing lysosomal degradation of the LDL receptor (LDLR) in the liver and thereby reducing LDL clearance. Here, we show that liver heparan sulfate proteoglycans are PCSK9 receptors and essential for PCSK9-induced LDLR degradation. The heparan sulfate-binding site is located in the PCSK9 prodomain and formed by surface-exposed basic residues interacting with trisulfated heparan sulfate disaccharide repeats. Accordingly, heparan sulfate mimetics and monoclonal antibodies directed against the heparan sulfate-binding site are potent PCSK9 inhibitors. We propose that heparan sulfate proteoglycans lining the hepatocyte surface capture PCSK9 and facilitates subsequent PCSK9:LDLR complex formation. Our findings provide new insights into LDL biology and show that targeting PCSK9 using heparan sulfate mimetics is a potential therapeutic strategy in coronary artery disease.PCSK9 interacts with LDL receptor, causing its degradation, and consequently reduces the clearance of LDL. Here, Gustafsen et al. show that PCSK9 interacts with heparan sulfate proteoglycans and this binding favors LDLR degradation. Pharmacological inhibition of this binding can be exploited as therapeutic intervention to lower LDL levels.

TidsskriftNature Communications
Sider (fra-til)503
StatusUdgivet - 11 sep. 2017

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