Native state dynamics affects the folding transition of porcine pancreatic phospholipase A2

Kölbel, Knut; Weininger, Ulrich; Ihling, Christian; Mrestani-Klaus, Carmen; Ulbrich‐Hofmann, Renate

doi:10.1016/j.bpc.2015.06.007

Cited by 2 publications

(2 citation statements)

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“…This is mainly due to the fact that lipid membranes are also highly sensible to such thermodynamic variables, which govern the membrane phase and lipid packing . Besides, the special structure of PLA 2 undergoes a reversible folded–unfolded transition at high temperatures (∼83 °C) due to multiple disulfide bridges . Therefore, since our experiments were performed at temperatures below 45 °C and at constant pressure (3 atm), PLA 2 function should be predominantly regulated by the high susceptibility to membrane packing and lipid arrangement.…”

Section: Resultsmentioning

confidence: 99%

“…55 Besides, the special structure of PLA 2 undergoes a reversible folded−unfolded transition at high temperatures (∼83 °C) due to multiple disulfide bridges. 56 Therefore, since our experiments were performed at temperatures below 45 °C and at constant pressure (3 atm), PLA 2 function should be predominantly regulated by the high susceptibility to membrane packing and lipid arrangement. Lipid packing is intrinsically controlled by the synergy between the lipid headgroup and tail features, as observed on the T m changes by modifying the acyl chain length.…”

Section: Aids Differentially Alter Lipid-membrane Structuralmentioning

confidence: 99%

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Modulation of Phospholipase A₂ Membrane Activity by Anti-inflammatory Drugs

Jaramillo-Granada,

Li,

Flores Villarreal

et al. 2024

Langmuir

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The phospholipase A 2 (PLA 2 ) superfamily consists of lipolytic enzymes that hydrolyze specific cell membrane phospholipids and have long been considered a central hub of biosynthetic pathways, where their lipid metabolites exert a variety of physiological roles. A misregulated PLA 2 activity is associated with mainly inflammatory-derived pathologies and thus has shown relevant therapeutic potential. Many natural and synthetic anti-inflammatory drugs (AIDs) have been proposed as direct modulators of PLA 2 activity. However, despite the specific chemical properties that these drugs share in common, little is known about the indirect modulation able to finely tune membrane structural changes at the precise lipid-binding site. Here, we use a novel experimental strategy based on differential scanning calorimetry to systematically study the structural properties of lipid membrane systems during PLA 2 cleavage and under the influence of several AIDs. For a better understanding of the AIDs-membrane interaction, we present a comprehensive and comparative set of molecular dynamics (MD) simulations. Our thermodynamic results clearly demonstrate that PLA 2 cleavage is hindered by those AIDs that significantly reduce the lipid membrane cooperativity, while the rest of the AIDs oppositely tend to catalyze PLA 2 activity to different extents. On the other hand, our MD simulations support experimental results by providing atomistic details on the binding, insertion, and dynamics of each AID on a pure lipid system; the drug efficacy to impact membrane cooperativity is related to the lipid order perturbation. This work suggests a membrane-based mechanism of action for diverse AIDs against PLA 2 activity and provides relevant clues that must be considered in its modulation.

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Section: Resultsmentioning

confidence: 99%

Section: Aids Differentially Alter Lipid-membrane Structuralmentioning

confidence: 99%