Tc toxin activation requires unfolding and refolding of a β-propeller

Nature. 2018 Nov;563(7730):209-213. doi: 10.1038/s41586-018-0556-6. Epub 2018 Sep 19.

Abstract

Tc toxins secrete toxic enzymes into host cells using a unique syringe-like injection mechanism. They are composed of three subunits, TcA, TcB and TcC. TcA forms the translocation channel and the TcB-TcC heterodimer functions as a cocoon that shields the toxic enzyme. Binding of the cocoon to the channel triggers opening of the cocoon and translocation of the toxic enzyme into the channel. Here we show in atomic detail how the assembly of the three components activates the toxin. We find that part of the cocoon completely unfolds and refolds into an alternative conformation upon binding. The presence of the toxic enzyme inside the cocoon is essential for its subnanomolar binding affinity for the TcA subunit. The enzyme passes through a narrow negatively charged constriction site inside the cocoon, probably acting as an extruder that releases the unfolded protein with its C terminus first into the translocation channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / chemistry
  • ADP Ribose Transferases / metabolism
  • ADP Ribose Transferases / ultrastructure
  • Bacterial Toxins / biosynthesis
  • Bacterial Toxins / chemistry*
  • Bacterial Toxins / metabolism*
  • Cryoelectron Microscopy*
  • Cytotoxins / biosynthesis
  • Cytotoxins / chemistry
  • Cytotoxins / metabolism
  • Models, Biological
  • Models, Molecular
  • Multiprotein Complexes / biosynthesis
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Multiprotein Complexes / ultrastructure*
  • Photorhabdus / chemistry
  • Photorhabdus / ultrastructure*
  • Protein Conformation
  • Protein Refolding*
  • Protein Transport
  • Protein Unfolding*

Substances

  • Bacterial Toxins
  • Cytotoxins
  • Multiprotein Complexes
  • ADP Ribose Transferases