Fig. 6: Proposed activation mechanism for OMP binding to SurA.

In the absence of substrate SurA is predominantly in an auto-inhibited core-P1 closed conformation (top) with a minor population (~25%⁵³) of an active core-P1 open conformation (right). Binding of OMP substrates (red) to the two identified binding hotspots in the core and P1 domains enables activation of the chaperone and leads to OMP expansion (left). These dual binding sites recognise aromatic containing motifs (e.g., Ar-X-Ar) that are enriched in OMP sequences⁵⁷. Whether it is OMP binding to the core site, P1 site, or both, that leads to chaperone activation is currently not clear, though our results implicate P1 binding in this process (Fig. 4, Supplementary Fig. 13). Binding sites of both hotspots are accessible in the core-P1 closed state suggesting that auto-inhibition is due to repression of conformational dynamics of the core domain, rather than steric blocking, and that sequences linking binding motifs in intact unfolded OMP clients are important for chaperone activation. Expansion of the substrate and prevention of locally collapsed regions in the unfolded chain by activated SurA suggests a mechanism for delivery of the ‘linearised’ client to BAM for its vectorial folding into the OM^54,63.