Crystal structure of Schistosoma mansoni Peroxiredoxin I: insights into a general mechanism of assembly of stress-regulated chaperones

2-Cys peroxiredoxins (Prx) are thought to play two alternative roles in cell's physiology: under low oxidative stress they are thioredoxin-dependent peroxidases, whereas upon exposure to high concentrations of H2O2, they change their oligomerization state from low molecular weight form (LMW) to high molecular weight (HMW) ATP-independent chaperones. Neither the precise structure of HMW complexes nor the binding site for unfolded proteins has been yet identified. In this poster we present the 3D crystal structures of decameric, LMW form, of PrxI from Schistosoma mansoni, obtained under reducing conditions and neutral pH, and of its HMW form, obtained under non-reducing conditions and acidic pH. The HMW is constituted by two stacked decamers. Size exclusion chromatography and functional experiments confirmed that the former has peroxidase activity whereas the latter is the putative holdase. Analysing the structures and using computational methods, we were able to explain the stacking of decamers (and thereby the switch between LMW and HMW) in terms of a quaternary change induced by tertiary structural variations occurring at the dimer-dimer interface. We suggest that environmental redox information is transmitted by hierarchical structural transitions that change the function of Prx through overoxidation of the sulphur atom of Cysp and unwinding of the first turn of the a5 helix. This event induces C-terminal arm unfolding and the concomitant protrusion of a loop towards the nearby dimer, triggering the quaternary structural change at the basis of the formation of the HMW form. Our structures provide also a model by which members of the Prx protein family form long filaments of stacked rings in vivo and enables us to propose how the HMW forms acquire the capability to bind non-native proteins.