Actin stabilizing compounds show specific biological effects due to their binding mode

Wang, Shuaijun; Crevenna, Alvaro H.; Ugur, Ilke; Marion, Antoine; Antes, Iris; Kazmaier, Uli; Hoyer, Maria; Lamb, Don C.; Gegenfurtner, Florian; Kliesmetes, Zane; Ziegenhain, Christoph; Enard, Wolfgang; Vollmar, Angelika and Zahler, Stefan (2019): Actin stabilizing compounds show specific biological effects due to their binding mode. In: Scientific Reports, Vol. 9, 9731

Abstract

Actin binding compounds are widely used tools in cell biology. We compare the biological and biochemical effects of miuraenamide A and jasplakinolide, a structurally related prototypic actin stabilizer. Though both compounds have similar effects on cytoskeletal morphology and proliferation, they affect migration and transcription in a distinctive manner, as shown by a transcriptome approach in endothelial cells. In vitro, miuraenamide A acts as an actin nucleating, F-actin polymerizing and stabilizing compound, just like described for jasplakinolide. However, in contrast to jasplakinolide, miuraenamide A competes with cofilin, but not gelsolin or Arp2/3 for binding to F-actin. We propose a binding mode of miuraenamide A, explaining both its similarities and its differences to jasplakinolide. Molecular dynamics simulations suggest that the bromophenol group of miurenamide A interacts with residues Tyr133, Tyr143, and Phe352 of actin. This shifts the D-loop of the neighboring actin, creating tighter packing of the monomers, and occluding the binding site of cofilin. Since relatively small changes in the molecular structure give rise to this selectivity, actin binding compounds surprisingly are promising scaffolds for creating actin binders with specific functionality instead of just "stabilizers".

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Pharmacy
• Research Centers: Center for NanoScience (CENS)
• Subjects: 500 Science > 540 Chemistry; 500 Science > 500 Science
• ISSN: 2045-2322
• Language: English