Latrunculin resistance mechanism of non-conventional actin NAP1 uncovered by molecular dynamics simulations.

Monomeric G-actin polymerizes into F-actin to perform various cellular functions. Actin depolymerization drugs, such as latrunculin-A (Lat-A), inhibit filament formation and disrupt the cytoskeleton. Interestingly, the green algae Chlamydomonas alternatively produces a non-conventional actin, NAP1, that responds to inhibition by latrunculin. However, the molecular mechanism underlying latrunculin resistance of NAP1 remains unclear because of the difficulty due to its low in vitro polymerizability. Instead of biochemical experiments, we performed molecular dynamics (MD) simulations to investigate whether NAP1 has a lower affinity for Lat-A than the conventional actins. Our phylogenetic comparison of the binding free energies shows that Lat-A is evolutionarily optimized for skeletal muscles. By decomposing the binding free energy into each amino acid residue, we found that some residues in NAP1 play an important role in latrunculin resistance, suggesting that the primary mechanism of latrunculin resistance is the loss of affinity for Lat-A due to substitutions. In conclusion, our binding-free-energy calculations using MD simulations provide the critical insight that loss of affinity is the direct mechanism of latrunculin resistance. © 2023 Wiley Periodicals LLC.

Citation

Rikuri Morita, Yasuteru Shigeta, Ryuhei Harada. Latrunculin resistance mechanism of non-conventional actin NAP1 uncovered by molecular dynamics simulations. Cytoskeleton (Hoboken, N.J.). 2024 Feb-Mar;81(2-3):143-150

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PMID: 37815120

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