Abstract
Pore-forming toxins (PFT) are virulence factors that transform from soluble to membrane-bound states. The Yersinia YaxAB system represents a family of binary α-PFTs with orthologues in human, insect, and plant pathogens, with unknown structures. YaxAB was shown to be cytotoxic and likely involved in pathogenesis, though the molecular basis for its two-component lytic mechanism remains elusive. Here, we present crystal structures of YaxA and YaxB, together with a cryo-electron microscopy map of the YaxAB complex. Our structures reveal a pore predominantly composed of decamers of YaxA–YaxB heterodimers. Both subunits bear membrane-active moieties, but only YaxA is capable of binding to membranes by itself. YaxB can subsequently be recruited to membrane-associated YaxA and induced to present its lytic transmembrane helices. Pore formation can progress by further oligomerization of YaxA–YaxB dimers. Our results allow for a comparison between pore assemblies belonging to the wider ClyA-like family of α-PFTs, highlighting diverse pore architectures.
Highlights
Pore-forming toxins (PFT) are virulence factors that transform from soluble to membranebound states
Prominent examples of heterooligomeric α-PFTs are the large tripartite insecticidal toxin complexes (Tc)[19,20,21]. These syringe-like assemblies consist of a homopentameric pore-forming subunit (TcA), and the TcB/TcC pair, which docks onto the TcA pore and contains the ADP-ribosyltransferase toxin cargo to be injected into susceptible cells[21]
Based on sequence and structural similarities to the well-characterized α-PFT Cytolysin A (ClyA)[12], the toxin components Hbl-B and NheA from B. cereus were classified within the ClyA family of α-PFTs25, 26
Summary
Pore-forming toxins (PFT) are virulence factors that transform from soluble to membranebound states. The two protein components share some 30% sequence identity and undergo similar conformational transitions from soluble to pore states. Another example is pleurotolysin, a two-component β-PFT from the edible oyster mushroom[17, 18]. Prominent examples of heterooligomeric α-PFTs are the large tripartite insecticidal toxin complexes (Tc)[19,20,21] These syringe-like assemblies consist of a homopentameric pore-forming subunit (TcA), and the TcB/TcC pair, which docks onto the TcA pore and contains the ADP-ribosyltransferase toxin cargo to be injected into susceptible cells[21]. The binary XaxAB toxin—discovered in entomopathogenic Xenorhabdus nematophila as a PFT27—represents a structurally uncharacterized family of α-PFT, with XaxA bearing low sequence similarity to ClyA and Hbl-B. Our structures enable the first direct comparison between pores of the wider ClyA family of α-PFTs, highlighting diverse toxin architectures
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