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Contribution to the understanding of the pathophysiology of Listeria monocytogenes

Left: 3D structure of PC-PLC. Right: Synergistic effect of PC-PLC on LLO membrane binding and pore formation.


Unique structure of Listeria monocytogenes phospholipase C

Listeriosis is one of the deadliest foodborne diseases caused by the intracellular bacterium Listeria monocytogenes (Lm). Although it is a relatively rare disease, the mortality rate for listeriosis is high, reaching 20–30 %. Because the bacterium also infects wild and domestic animals, it poses a serious challenge to the food and agricultural industries worldwide. Infection by Lm is facilitated by a plethora of specialized bacterial effectors. Its two major virulence factors, broad-range phospholipase C (PC-PLC) and the pore-forming toxin listeriolysin O (LLO), enable the bacterium to spread in the host by destroying cell membranes. PC-PLC is a zinc metalloenzyme and LLO is the cholesterol-dependent pore-forming toxin listeriolysin O (LLO).

Insights into the atomic structures and molecular mechanisms of action of virulence factors are a prerequisite for understanding the progression of diseases and developing alternative solutions for their control. In this study, we determined the crystal structure of PC-PLC, which reveals distinctive structural features in an otherwise conserved PC-PLC fold that regulate its activity. These include the invariant position of the N-terminal tryptophan (W1), the structurally plastic active site, Zn2+-dependent activity, and the tendency to form oligomers with impaired enzymatic activity. Furthermore, we demonstrate that the phospholipase activity of PC-PLC can be specifically inhibited by its propeptide added in trans. This may serve as a basis for the development of highly specific inhibitors of this important virulence factor.

Finally, we describe the synergistic activity of PC-PLC and the pore-forming toxin LLO at the molecular level. We show enhanced binding of LLO to vesicles pretreated with PC-PLC. Moreover, PC-PLC enhances the pore-forming activity of LLO and affects the morphology of LLO oligomerization on lipid membranes, revealing the multifaceted synergy of the two virulence factors.

In summary, the article presents the unique structure of the important virulence factor PC-PLC and describes its structural details in comparison with its homologs from other extracellular bacteria. It also shows how structural details, together with inhibition by the propeptide (in cis or trans) and oligomer formation represent autoregulatory mechanisms for PC-PLC. Finally, it reveals a synergistic interaction of PC-PLC and LLO that has important implications for the pathophysiology of Lm.


For further information please contact: marjetka.podobnik(at)




Left: 3D structure of PC-PLC. Right: Synergistic effect of PC-PLC on LLO membrane binding and pore formation. Unique…
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