Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex
Ying Huang, … , Ulf Landmesser, Stanley L. Hazen
Ying Huang, … , Ulf Landmesser, Stanley L. Hazen
Published August 1, 2013
Citation Information: J Clin Invest. 2013;123(9):3815-3828. https://doi.org/10.1172/JCI67478.
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Research Article Cardiology

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

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Figure 7

Structural model of a hypothetical ternary complex of MPO and PON1 bound to nHDL.

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Structural model of a hypothetical ternary complex of MPO and PON1 bound...
Illustration of an HDL-MPO-PON1 ternary complex composed of the double superhelix model of nHDL and the crystal structures of MPO and PON1 bound to one another with identified protein-protein interaction sites. The two predominantly α helical APOA1 chains in nHDL are aligned in a head-to-tail antiparallel arrangement. N-termini are shown in dark red/blue, and C-termini are shown in light red/blue. Phospholipids in the lipid core of nHDL are depicted in semitransparent green. PON1 binding sites on APOA1 shown are P1 (L38-L46, solid blue) and P2 (S201-K208, solid light red). Adjacent MPO binding site on APOA1 (residues A190-L203, filled light blue) is also depicted. Site-specific oxidative modifications found in PON1 recovered from isolated HDL from either atherosclerotic lesions or ACS plasma include Tyr71 (red) and Met55 and Met88 (both green). Met12 of PON1 is not shown because the N terminus (16 amino acids) of PON1 was not resolved in the PON1 crystal structure reported. Location of the openings to the two heme pockets on the MPO homodimer are predicted to be in close spatial proximity to the site-specific oxidative modifications reported in APOA1 recovered from human atherosclerotic plaque, Tyr166, and Tyr192 (solid black). Also shown are the “solar flare” regions of APOA1, presumed LCAT interaction sites (solid yellow).