Toggle switch residues control allosteric transitions in bacterial adhesins by participating in a concerted repacking of the protein core

• DOI: 10.1371/journal.ppat.1009440
• Publication Date: 2021-04-07T18:54:21Z
• Authors: Dagmara I. Kisiela; Pearl Magala; Gianluca Interlandi; Laura A. Carlucci; Angelo Ramos; Veronika Tchesnokova; Benjamin Basanta; Vladimir Yarov-Ya...; Hovhannes Avagyan; Anahit Hovhannisyan; Wendy E. Thomas; Ronald E. Stenkamp; Rachel E. Klevit; Evgeni V. Sokurenko
• Keywords: Alanine

Critical molecular events that control conformational transitions in most allosteric proteins are ill-defined. The mannose-specific FimH protein of Escherichia coli is a prototypic bacterial adhesin switches from an ‘inactive’ low-affinity state (LAS) to ‘active’ high-affinity (HAS) conformation allosterically upon mannose binding and mediates shear-dependent catch bond adhesion. Here we identify novel type antibody acts as kinetic trap prevents the transition between conformations both directions. Disruption significantly slows FimH’s ability associate with blocks adhesion under dynamic conditions. residues critical for form compact epitope located away mannose-binding pocket structurally conserved states. A larger antibody-FimH contact area identified by NMR contains Leu-34 Val-35 move core-buried surface-exposed orientations opposing directions during transition. Replacement charged glutamic acid stabilizes LAS replacement traps HAS conformation. unable if replaced less bulky alanine. We propose these act toggle bound imposes steric block their reorientation either direction, thereby restricting concerted repacking side chains must occur enable Residues homologous highly across diverse family fimbrial adhesins. predicted switch reveals another E . adhesin, galactose-specific FmlH, can shift inactive active state. Our study shows adhesins depend on effectively disables adhesive function.