Conformational Dynamics and Activation of Membrane-Associated Human Group IVA Cytosolic Phospholipase A 2 (cPLA 2 )
Year: 2025
Type: article
Abstract: Cytosolic phospholipase A 2 (cPLA 2 ) associates with membranes where it hydrolyzes phospholipids containing arachidonic acid to initiate an inflammatory cascade. All-atom molecular dynamics simulations were employed to understand the activation process when cPLA 2 associates with the endoplasmic reticulum (ER) membrane of macrophages where it acts. We found that membrane association causes the lid region of cPLA 2 to undergo a closed-to-open state transition that is accompanied by the sideways movement of loop 495-540, allowing the exposure of a cluster of lysine residues (K488, K541, K543, and K544), which binds the allosteric activator PIP 2 in the membrane. The active site of the open form of cPLA 2 , containing the catalytic dyad residues S228 and D549, exhibited a three-fold larger cavity than the closed form of cPLA 2 in aqueous solution. These findings provide mechanistic insight as to how cPLA 2 ER membrane association promotes major transitions between conformational states critical to allosteric activation and enzymatic phospholipid hydrolysis.
Institution: University of California San Diego
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W4411135821