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Towards the application of Tc toxins as a universal protein translocation system

Daniel Roderer1, Evelyn Schubert1, Oleg Sitsel1

  • 1Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227, Dortmund, Germany.

Nature Communications
|November 22, 2019
PubMed

Insights

Bacterial Tc toxins can be engineered as customizable molecular syringes. Researchers demonstrated that various proteins can replace the native toxic enzyme for targeted delivery across membranes.

Area of Science:

  • Bacteriology
  • Molecular Biology
  • Structural Biology

Background:

  • Toxins-associated secretion (Tc) toxins are bacterial protein complexes employing a syringe-like mechanism to deliver cytotoxic enzymes into target cells.
  • Tc toxins consist of a membrane translocator and a protective cocoon housing a variable toxic enzyme, which differs across species.

Purpose of the Study:

  • To investigate the feasibility of replacing the native toxic enzyme in Tc toxins with heterologous proteins.
  • To establish Tc toxins as a versatile platform for delivering diverse proteins across cellular membranes.

Main Methods:

  • Utilized electron microscopy and X-ray crystallography to analyze Tc toxin structure and interactions.
  • Performed in vitro translocation assays to assess the delivery efficiency of engineered Tc toxins.

Main Results:

  • Demonstrated successful replacement of the native toxic enzyme with various proteins, including Cdc42, ICP47, iLOV, DHFR, CRAF kinase domain, and TEV protease.
  • Confirmed the ability of Tc toxins to function as customizable molecular syringes for protein delivery.
  • Identified key protein characteristics (size, charge, fold) essential for successful translocation.

Conclusions:

  • Tc toxins can be engineered as adaptable molecular delivery systems.
  • The findings provide guidelines for utilizing Tc toxins as a universal protein translocation platform.
  • This research opens avenues for novel therapeutic and research applications involving targeted protein delivery.

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