Secreted Phospholipase A2 Inhibitors Are Also Potent Blockers of Binding to the M-Type Receptor

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• 作者：Eric Boilard ; Morgane Rouault ; Fanny Surrel ; Catherine Le Calvez ; Sofiane Bezzine ; Alan Singer ; Michael H. Gelb ; Gé ; rard Lambeau
• 刊名：Biochemistry
• 出版年：2006
• 出版时间：November 7, 2006
• 年：2006
• 卷：45
• 期：44
• 页码：13203 - 13218
• 全文大小：772K
• 年卷期：v.45,no.44(November 7, 2006)
• ISSN：1520-4995

文摘

Mammalian secreted phospholipases A₂ (sPLA₂s) constitute a family of structurally relatedenzymes that are likely to play numerous biological roles because of their phospholipid hydrolyzing activityand binding to soluble and membrane-bound proteins, including the M-type receptor. Over the past decade,a number of competitive inhibitors have been developed against the inflammatory-type human group IIA(hGIIA) sPLA₂ with the aim of specifically blocking its catalytic activity and pathophysiological functions.The fact that many of these inhibitors, including the indole analogue Me-Indoxam, inhibit several othersPLA₂s that bind to the M-type receptor prompted us to investigate the impact of Me-Indoxam and otherinhibitors on the sPLA₂-receptor interaction. By using a Ca²⁺ loop mutant derived from a venom sPLA₂which is insensitive to hGIIA inhibitors but still binds to the M-type receptor, we demonstrate that Me-Indoxam dramatically decreases the affinity of various sPLA₂s for the receptor, yet an sPLA₂-Me-Indoxam-receptor complex can form at very high sPLA₂ concentrations. Me-Indoxam inhibits the bindingof iodinated mouse sPLA₂s to the mouse M-type receptor expressed on live cells but also enhances bindingof sPLA₂ to phospholipids. Because Me-Indoxam and other competitive inhibitors protrude out of thesPLA₂ catalytic groove, it is likely that the inhibitors interfere with the sPLA₂-receptor interaction bysteric hindrance and to different extents that depend on the type of sPLA₂ and inhibitor. Our findingsuggests that the various anti-inflammatory therapeutic effects of sPLA₂ inhibitors may be due not onlyto inhibition of enzymatic activity but also to modulation of binding of sPLA₂ to the M-type receptor orother as yet unknown protein targets.