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Sorenson, RC, Bisgaier, CL, Aviram, M, Hsu, C, Billecke, S and La Du, BN (1999) Human serum Paraoxonase/Arylesterase's retained hydrophobic N-terminal leader sequence associates with HDLs by binding phospholipids : apolipoprotein A-I stabilizes activity. Arterioscler. Thromb. Vasc. Biol. 19:2214-25


In serum, human paraoxonase/arylesterase (PON1) is found exclusively associated with high density lipoprotein (HDL) and contributes to its antiatherogenic properties by inhibiting low density lipoprotein (LDL) oxidation. Difficulties in purifying PON1 from apolipoprotein A-I (apoA-I) suggested that PON1's association with HDL may occur through a direct binding between these 2 proteins. An unusual property of PON1 is that the mature protein retains its hydrophobic N-terminal signal sequence. By expressing in vitro a mutant PON1 with a cleavable N-terminus, we demonstrate that PON1 associates with lipoproteins through its N-terminus by binding phospholipids directly rather than binding apoA-I. Nonetheless, apoA-I stabilized arylesterase activity more than did phospholipid alone, apoA-II, or apoE. Consequently, we studied the role of apoA-I in PON1 expression and HDL association in mice genetically deficient in apoA-I. Though present in HDL fractions at decreased levels, PON1 arylesterase activity was less stable than in control mice. Furthermore, PON1 could be competitively removed from HDL by phospholipids, suggesting that PON1's retained N-terminal peptide allows transfer of the enzyme between phospholipid surfaces. Thus, our data suggest that PON1 is stabilized by apoA-I, and its binding to HDL and physiological distribution are dependent on the direct binding of the retained hydrophobic N-terminus to phospholipids optimally presented in association with apoA-I.




Animals; Apolipoprotein A-I/physiology; Aryldialkylphosphatase; Binding, Competitive; Carboxylic Ester Hydrolases/blood; Carboxylic Ester Hydrolases/genetics; Carboxylic Ester Hydrolases/metabolism; Carboxylic Ester Hydrolases/physiology; Cell Line; Cholesterol, HDL/metabolism; Detergents/metabolism; Esterases/blood; Esterases/genetics; Esterases/metabolism; Esterases/physiology; Female; Humans; Lipoproteins/blood; Lipoproteins/metabolism; Lipoproteins, LDL/metabolism; Male; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Peptide Fragments/genetics; Peptide Fragments/metabolism; Peptide Fragments/physiology; Phospholipids/metabolism; Phospholipids/pharmacology; Proteolipids/metabolism



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status



GO:0034364: high-density lipoprotein particle

ECO:0000304: author statement supported by traceable reference used in manual assertion


Seeded From UniProt




GO:0005543: phospholipid binding

ECO:0000314: direct assay evidence used in manual assertion


Seeded From UniProt


See also


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