Journal:IUCrJ:S2052252524001969

The ABC Toxin Complex from Yersinia entomophaga Can Package a Cytotoxin Expressed from an “Orphan” Genetic Locus: the Structures of Both the RHS Shell and its Cargo.

Jason N. Busby, Sarah Trevelyan, Cassandra L. Pegg, Edward D. Kerr, Benjamin L. Schulz, Irene Chassagnon, Michael J. Landsberg, Mitchell K. Weston, Mark R. H. Hurst, and J. Shaun Lott ^[1]

Molecular Tour
The “ABC” toxins are a type of protein toxin found in many bacteria, named after the three main protein components, which are produced from three adjacent genes labelled A, B and C. Structural analyses over the past decade have revealed the delivery mechanism of these toxins in great detail. The A component forms an injection apparatus, whereas the B and C components together form a hollow, eggshell-like structure that encloses the unfolded, toxic “cargo” that is encoded by the C-terminal sequence of the C protein. When the fully assembled ABC complex attaches to the surface of target eukaryotic cells, the A subunit penetrates the membrane with a syringe-like injection device, delivering the cargo into the cell, where it folds into its active cytotoxic form.

The BC shell structure is constructed of multiple copies of peptide motif known as the RHS repeat. RHS-repeat shells are able to enclose a wide range of proteins, with no clear sequence-based specificity. Hence, different ABC complexes deliver a different toxic cargoes. However, the toxic cargoes themselves are poorly structurally characterised, with only one experimentally determined structure known to date.

In this paper we describe the structure of a BC shell from an insecticidal bacterium where the C component is produced from a gene that is distant in the genome from the known ABC genetic locus, an example of an “orphan” toxin gene. We also determine the structure of the toxin cargo, which shows it to likely be an ADP-ribosyltransferase that modifies actin in the target cell, preventing actin polymerisation and hence triggering apoptotic cell death. We show that the native toxin isolated from the bacterium contains multiple toxic cargoes, showing that in vivo, a range of toxic proteins can be delivered using this shared mechanism.

The crystal structure of YenB/YenC3^NTD (PDB code 5kis). YenB is highlighted in green and YenC3^NTD in blue. YenB and YenC3 are the yenB and yenC3 gene products from Yersinia entomophaga; NTD is N-terminal domain. Vertical slice through showing the internal cavity of YenB/YenC3^NTD.

The crystal structure of YenC3^CTD (PDB code 6aqk) coloured from blue at the N-terminus to red at the C-terminus, showing the key catalytic residues (R839, S881 and E919) as spheres. CTD is C-terminal domain.

References

1. ↑ doi: https://dx.doi.org/10.1107/S2052252524001969