Deciphering the structural intricacy in virulence effectors for proton-motive force mediated unfolding and type-III protein secretion
2019
Many gram-negative pathogenic bacteria use type III secretion system (T3SS) to inject virulence effectors directly into the cytosol of targeted host cells. Given that the protein unfolding requisite for secretion via nano-size pore of T3SS injectisome is an energetically unfavorable process, How do pathogenic bacteria unfold and secrete hundreds of toxic proteins in seconds remain largely unknown. In this study, first, from an in-depth analysis of folding and stability of T3SS effector ExoY, we show that the proton-concentration gradient (~pH 5.8-6.0) generated by proton-motive force (PMF) can significantly amortize tertiary structural folding and stability of effectors without significant entropic cost. Strikingly, it was found that the lower energetic cost associated with the global unfolding of ExoY is mainly due to its weakly folded geometry and abundance of geometrical frustrations stemming from buried water molecules and native-like folded intermediates in the folded cores. From in-silico structural analysis of 371 T3SS effectors, it can be curtained that T3SS effectors belong to typical class (disorder globules) of IDPs and have evolved similar conserved intrinsic structural archetypes to mediate early-stage unfolding. The slower folding kinetics in effector proteins requisite for efficient T3SS-mediated secretion mostly stems from reduced hydrophobic density and enhanced polar-polar repulsive interactions in their sequence landscapes. Lastly, the positively evolved histidine-mediated stabilizing interactions and gate-keeper residues in effector proteins shed light on collaborative role of evolved structural chemistry in T3SS effectors and PMF in the spatial-temporal regulation of effector folding and stability essential for maintaining balance in secretion and function trade-off.
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