Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex
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
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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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 5

PON1 Tyr71 is a functionally important site for HDL interaction and a target for MPO-catalyzed oxidation in human atherosclerotic plaque.

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PON1 Tyr71 is a functionally important site for HDL interaction and a ta...
(A) Schematic illustration of photocholestanyl-labeled PON1 tyrosyl residue. (B) Reconstituted HDL formed using POPC/photocholesterol/APOA1 (100:10:1) was incubated with PON1 and exposed to UV light as described in Methods. Proteomics studies revealed the photocholestanyl adduct of PON1 Tyr71 [Y(ch)] as a site on PON1 that directly interacts with cholesterol as described in Methods. m/z, mass-to-charge ratio. (C) PON1 crystal structure with superimposed location of Tyr71 (red) and hypothetical HDL binding surface based on hydrophobicity analysis. (D) Recombinant human WT PON1 versus the indicated PON1 Tyr71 site–specific mutants were generated, isolated, incubated with HDL, and then paraoxonase activity was determined as described in Methods. Results represent the mean ± SD from at least 3 independent experiments.