This advanced approach revealed a specific peptide region consisting of two alpha helices connected with a loop that acts as a gate to the enzyme’s active site. Typically, this gate is in a “closed” position, but when Lp-PLA2 binds to the phospholipid membrane, it undergoes an allosteric conformational change that opens the gate and increases the volume of the active site.
Dennis’ team, led by first author Varnavas D. Mouchlis, Ph.D., also showed which oxidized phospholipid substrates Lp-PLA2 has the greatest affinity for. The team also identified a binding pocket that was distinct from the known drug inhibitor binding pockets. This could be a potential target for future therapeutic drugs.
This study is the latest in an ongoing series of studies by the Dennis lab to create a unifying theory about the function of phospholipases. The group had previously introduced this concept of membrane-facilitated allosteric regulation of PLA2 enzymes, but had until this point only studied enzymes that function on phospholipid bilayers (as seen on cells and intracellular organelles). This study confirmed th