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Friday, December 02, 2022

Mechanism of bacterial toxins in lethal attacks: Cryo-EM and protein NMR 3D snapshots reveal sophisticated mechanism of action of a bacterial TC toxin

Only one-thousandth of a milligram of bacterial botulinum toxin is needed to kill a living organism. The venom exerts its lethal effect by inhibiting the release of neurotransmitters at the point where nerve cells attach to muscles, thereby paralyzing them. As simple as this process may sound, it is actually a sophisticated and multi-step process. No less complex and indeed very effective is the intoxication process of toxin complexes (TCs), virulence agents of many bacteria, including insect and human pathogens.

A bacterial syringe delivers a deadly enzyme

The mechanism of action of TC toxins has recently been uncovered to a large extent by the work of Stefan Raunser’s team in structural biology at MPI Dortmund. “Uncovering the structure of Tc toxin subunits and their assembly by cryo electron microscopy (cryo-EM) helped us understand the key steps of toxin activation and membrane penetration,” says Raunser. The scientists showed that the subunits of the Tc toxin complex act together like a syringe: once the subunits are assembled, structural changes in the complex trigger the opening of a cocoon containing a toxic enzyme, which is then Secreted in a unique injection apparatus. A channel in the host cell. There, it exerts its deleterious effect by impairing the regulation of the cell’s cytoskeleton, which consists of a network of polymerized actin (F-actin) filaments involved in many essential cellular processes.

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Setting up the opponent by reducing the striking distance

“For a long time, we struggled to get a complete picture of the intoxication process, because we lacked structural data on secreted enzymes, one of which is TccC3,” reflects Raunser. Until recently, it was only known that TccC3 transfers an ADP-ribose group to actin, which promotes its aberrant polymerization, leading to actin filament clumping. “TccC3 is what we call a “difficult” system for structural investigation because of its size and high flexibility,” says Hartmut Oskinat. “By simply applying solution NMR, we can overcome this challenge and visualize the 3D structure of proteins for the first time.” By fusing two more cryo-EM snapshots of TCCC3 bound to F-actin and modified F-actin alone, scientists have uncovered the enzyme’s unique mechanism of action. “TccC3 acts like a boxer to make his opponent vulnerable to attack,” says Stephen Raunser. In the first step, the enzyme binds to the region between two consecutive actin subunits of F-actin. TccC3 then opens a gate, which brings the molecule NAD+ containing an ADP-ribose group within striking distance to a reactive site on actin. Once the bulky ADP-ribose group is transferred to F-actin, it is no longer accessible to its depolymerizing factors, allowing F-actin to no longer be broken down and thus clumps .

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In addition to this discovery, the scientists’ findings have helped formulate an explanation for the enzyme’s surprisingly high efficiency. When the enzyme dissociates from F-actin, its gate mechanism prevents a nonspecific recombination to a previously modified actin as a preparation for the next attack. “It’s amazing how all of these mechanisms evolved to maximize the potency of toxins. And nature did a pretty good job because botulinum toxins, ricin, and other biotoxins are still considered the most toxic substances,” says Raunser. concluded.

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material provided by Max Planck Institute of Molecular Physiology, Note: Content can be edited for style and length.

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