Dose-dependent effect of cyclophosphamide treatment on actin

Abstract

The actin is the essential unit protein of cytoskeleton and muscle sarcomeres. The continuous management of filaments is the key machinery of eukaryotic cytoskeletal plasticity which based on the different complexes with divalent cations (Ca2+ or Mg2+) and nucleotides (ATP, ADP). Any structural modification of nucleotide-binding sites in G actin can bind ATP or ADP under different cation conditions and can initialize the remodelling of the cleft and change the stiffness of two main domains. The evolutionary important nucleotide-binding cleft as a bridge between the two domains needs more investigation to can express its importance in the development of actin functions. The cyclophosphamide (CP) is a cytostatic drug applied in chemotherapy it can alkylate the long residues in the ATP binding sites thus change the structure of the binding cleft. Our previous study explained that the actin filaments show less sensitivity to the CP treatment than monomers. Here we investigate the CP dose-response effect on the thermodynamic stability of actin monomers and polymers in the presence of Ca2+ or Mg2+ to know the minimum effective concentration for the interpretation of any relevant dosage at level of tissues. The previously expressed “titled state” EM model of filamentous actin based on the same structural change of monomers as we found here where the domains react to any modification with taking apart sd4 from sd2 results in a more exposed nucleotide-binding cleft.