Crystal Structure of a Schistosoma mansoni Septin Reveals the Phenomenon of Strand Slippage in Septins Dependent on the Nature of the Bound Nucleotide

Background: Septins are filament-forming proteins involved in membrane-remodeling events. Results: Two crystal structures of a septin with the highest resolution to date reveal the phenomenon of -strand slippage. Conclusion: A novel mechanistic framework for the influence of the nature of the bound nucleotide and the presence of Mg2+ in septins is proposed. Significance: Identification of strand slippage might contribute to elucidating the mechanism of septin association with membranes. Septins are filament-forming GTP-binding proteins involved in important cellular events, such as cytokinesis, barrier formation, and membrane remodeling. Here, we present two crystal structures of the GTPase domain of a Schistosoma mansoni septin (SmSEPT10), one bound to GDP and the other to GTP. The structures have been solved at an unprecedented resolution for septins (1.93 and 2.1 , respectively), which has allowed for unambiguous structural assignment of regions previously poorly defined. Consequently, we provide a reliable model for functional interpretation and a solid foundation for future structural studies. Upon comparing the two complexes, we observe for the first time the phenomenon of a strand slippage in septins. Such slippage generates a front-back communication mechanism between the G and NC interfaces. These data provide a novel mechanistic framework for the influence of nucleotide binding to the GTPase domain, opening new possibilities for the study of the dynamics of septin filaments.