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

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”.

Cryo‐EM Resolves Molecular Recognition Of An Optojasp Photoswitch Bound To Actin Filaments In Both Switch States

“…This does not only result in a better fit and higher activity for the cis ‐isomer, but also in switching the F‐actin into a state resembling the phalloidin‐bound form. This conformational modulation of the whole F‐actin offers interesting explanations for different in cellulo activities observed previously for F‐actin ligands [6, 26] . Such effects may now be further explored by structure‐based optimization of the optojasps.…”

“…The close resemblance of the F‐actin bound cis ‐ 3 and phalloidin, as well as the presence of the closed D‐loop state, suggests that both ligands do not stabilize the open D‐loop state to the same extent as JASP or trans ‐ 3 . Such ligand‐induced modulation may have relevance for the functional difference of F‐actin stabilizing compounds [26] . We have previously shown that the addition of JASP to F‐actin‐ADP results in strong binding of coronin‐1B, which is usually limited to F‐actin‐ADP‐P i [2] .…”

“…Such ligandinduced modulation may have relevance for the functional difference of F-actin stabilizing compounds. [26] We have previously shown that the addition of JASP to F-actin-ADP results in strong binding of coronin-1B, which is usually limited to F-actin-ADP-P i . [2] Based on this, we proposed that nucleotide-sensitive ABPs such as coronin distinguish the nucleotide state of F-actin based on the conformation of the D-loop, [2] which serves as a hub for ABP binding.…”

“…This conformational modulation of the whole F-actin offers interesting explanations for different in cellulo activities observed previously for F-actin ligands. [6,26] Such effects may now be further explored by structure-based optimization of the optojasps. In combination, our data showcase the impact that cryo-EM can have on understanding drug functioning on complex protein targets as well as on structure determination of ligands not accessible by Xray crystallography, opening up new prospects for structure-based drug design.…”

Recent Advances in Small Peptides of Marine Origin in Cancer Therapy

“…However, some of those researched have an anticancer mechanism for a specific cancer cell. Jaspamide (jasplakinolide, NSC-613009, Table 2 and Figure 4 ), isolated from the sponge, Jaspis Johnstoni in 1986, has been considered a classical actin stabilizer [ 84 ]. Jaspamide-induced apoptosis is associated with caspase-3 activation, and increased Bax level, and decreased Bcl-2 protein expression.…”