Abstract Actin's C-terminus contributes to interactions with actin binding proteins (ABPs) in cellular processes. Historical resolution constraints have prevented a complete understanding of how actin's C-terminus mediates actin's interactions, but evidence suggested that it undergoes conformational shifts upon ABP binding. Actin's C-terminus also shifts in response to actin's nucleotide state, guiding nucleotide dependent ABP binding. Previously, we proposed that C-terminal shifts regulate actin's functions through allosteric communication networks. To further examine the role of C-terminal shifts in actin communication networks and understand how C-terminal modifications influence actin's functional state, we utilized in silico modelling of actin filaments crosslinked by N,N'-para-phenylenebismaleimide (PBM). Our modelling examined how constraining C-terminal flexibility with PBM crosslinks affects the conformation of distant structural elements and shifts internal communication networks critical for actin's functions. We present evidence that disruption of the stabilizing F375-R116 interaction by PBM-crosslinks reshapes allosteric communication networks through the protomer, altering nucleotide cleft architecture and nucleotide dynamics. We therefore propose that actin's C-terminus acts as a nexus for actin structural changes, shifting in response to stimuli and propagating changes that allow actin to adopt different functional conformations that influence ABP binding.
Steffensen et al. (Wed,) studied this question.