Allostery and molecular stripping mechanism in profilin regulated actin filament growth

Abstract

Profilin is an actin-sequestering protein and plays key role in regulating the polarized growth of actin filament. Binding of profilin to monomeric actin (G-actin) allows continuous elongation at the barbed end, but not the pointed end, of filament. How G-actin exchanges between the profilin-sequestered state and the filament state (F-actin) to support the barbed end elongation is not well understood. Here, we investigate the involved molecular mechanism by constructing a multi-basin energy landscape model and performing molecular simulations. We showed that the actin exchanging occurs by forming a ternary complex. The interactions arising from the barbed end binding drive the conformational change of the attached G-actin in the ternary complex from twist conformation to more flatten conformation without involving the change of nucleotide state, which in turn destabilizes the actin-profilin interface and promotes the profilin stripping event through allosteric coupling. We also showed that attachment of free profilin to the barbed end induces conformational change of the barbed end actin and facilitates its stripping from the filament. These results suggest a molecular stripping mechanism of the polarized actin filament growth dynamics controlled by the concentrations of the actin-profilin dimer and the free profilin, in which the allosteric feature of the monomeric actin plays crucial role.

Effect of chaperone–client interaction strength on Hsp70-mediated protein folding

“…[21,43] By switching the double-basin energy function from ADP state to ATP state, it is possible to reasonably simulate the conformational transition of Hsp70 SBD from closed state to open state. [16][17][18]21] Similar energy function with double-basin topography has been successfully used in describing the ligand binding coupled folding and conformational motions of allosteric proteins, [28,41,44] the molecular mechanism of enzyme catalysis, [9,45,46] and filament assembly [47] in previous works. The energy function describing the hydrophobic interaction between the chaperone and substrate is given by [38,48] V…”