title: 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.affiliation: Department of Cellular and Molecular Medicine, Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wu
authors.forename: Meliana
authors.initials: M
authors.lastname: Riwanto
authors.forename: Shengqiang
authors.initials: S
authors.lastname: Gao
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Levison
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Gu
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Fu
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Wagner
authors.forename: Christian
authors.initials: C
authors.lastname: Besler
authors.forename: Gary
authors.initials: G
authors.lastname: Gerstenecker
authors.forename: Renliang
authors.initials: R
authors.lastname: Zhang
authors.forename: Xin-Min
authors.initials: XM
authors.lastname: Li
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: DiDonato
authors.forename: Valentin
authors.initials: V
authors.lastname: Gogonea
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
authors.forename: Diana M
authors.initials: DM
authors.lastname: Shih
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DiDonato
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D043303:Aryldialkylphosphatase / Q000737:chemistry / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D041961:Deuterium Exchange Measurement; D004795:Enzyme Stability; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000737:chemistry / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000201:enzymology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary
chemical_list: D008075:Lipoproteins, HDL; D009195:Peroxidase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human
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