Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex.

Abstract

Myeloperoxidase (MPO) and paraoxonase 1 (PON1) are high-density lipoprotein-associated (HDL-associated) proteins mechanistically linked to inflammation, oxidant stress, and atherosclerosis. MPO is a source of ROS during inflammation and can oxidize apolipoprotein A1 (APOA1) of HDL, impairing its atheroprotective functions. In contrast, PON1 fosters systemic antioxidant effects and promotes some of the atheroprotective properties attributed to HDL. Here, we demonstrate that MPO, PON1, and HDL bind to one another, forming a ternary complex, wherein PON1 partially inhibits MPO activity, while MPO inactivates PON1. MPO oxidizes PON1 on tyrosine 71 (Tyr71), a modified residue found in human atheroma that is critical for HDL binding and PON1 function. Acute inflammation model studies with transgenic and knockout mice for either PON1 or MPO confirmed that MPO and PON1 reciprocally modulate each other's function in vivo. Further structure and function studies identified critical contact sites between APOA1 within HDL, PON1, and MPO, and proteomics studies of HDL recovered from acute coronary syndrome (ACS) subjects revealed enhanced chlorotyrosine content, site-specific PON1 methionine oxidation, and reduced PON1 activity. HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, whereupon PON1 binding partially inhibits MPO activity, and MPO promotes site-specific oxidative modification and impairment of PON1 and APOA1 function.

• Authors: Ying Huang, Zhiping Wu, Meliana Riwanto, Shengqiang Gao, Bruce S Levison, Xiaodong Gu, Xiaoming Fu, Matthew A Wagner, Christian Besler, Gary Gerstenecker, Renliang Zhang, Xin-Min Li, Anthony J DiDonato, Valentin Gogonea, W H Wilson Tang, Jonathan D Smith, Edward F Plow, Paul L Fox, Diana M Shih, Aldons J Lusis, Edward A Fisher, Joseph A DiDonato, Ulf Landmesser, Stanley L Hazen
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 123 Issue 9 Pg. 3815-28 (Sep 2013) ISSN: 1558-8238 [Electronic] United States
• PMID: 23908111 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lipoproteins, HDL
• Peroxidase
• Aryldialkylphosphatase
• PON1 protein, human

Topics

• Amino Acid Sequence
• Animals
• Aryldialkylphosphatase (chemistry, metabolism)
• Case-Control Studies
• Cell Line
• Deuterium Exchange Measurement
• Enzyme Stability
• Humans
• Lipoproteins, HDL (chemistry, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oxidation-Reduction
• Peroxidase (chemistry, metabolism)
• Plaque, Atherosclerotic (enzymology)
• Protein Binding
• Protein Interaction Domains and Motifs
• Protein Structure, Secondary