Molecular basis of the interaction between plasma platelet-activating factor acetylhydrolase and low density lipoprotein

The platelet-activating factor acetylhydrolases are enzymes that were initi ally characterized by their ability to hydrolyze platelet-activating factor (PAF). In human plasma, PAF acetylhydrolase (EC 3.1.1.47) circulates in a complex with low density lipoproteins (LDL) and high density lipoproteins ( HDL). This association defines the physical state of PAF acetylhydrolase, c onfers a long half-life, and is a major determinant of its catalytic effici ency in vivo. The lipoprotein-associated enzyme accounts for all of the PAF hydrolysis in plasma but only two-thirds of the protein mass. To character ize the enzyme-lipoprotein interaction, we employed site-directed mutagenes is techniques. Two domains within the primary sequence of human PAF acetylh ydrolase, tyrosine 205 and residues 115 and 116, were important for its bin ding to LDL. Mutation or deletion of those sequences prevented the associat ion of the enzyme with lipoproteins. When residues 115 and 116 from human P AF acetylhydrolase were introduced into mouse PAF acetylhydrolase (which no rmally does not associate with LDL), the mutant mouse PAF acetylhydrolase a ssociated with lipoproteins, To analyze the role of apolipoprotein (apo) B1 00 in the formation of the PAF acetylhydrolase-LDL complex, we tested the a bility of PAF acetylhydrolase to bind to lipoproteins containing truncated forms of apoB, These studies indicated that the carboxyl terminus of apoB p lays a key role in the association of PAF acetylhydrolase with LDL. These d ata on the molecular basis of the PAF acetylhydrolase-LDL association provi de a new level of understanding regarding the pathway for the catabolism of PAF in human blood.