Work

Effector conformational plasticity enables lineage-specific secretion via Hcp heterohexamers in gut symbionts

Year: 2026

Type: article

Abstract: The Type VI Secretion System (T6SS) delivers effectors to mediate interbacterial competition. While the conserved hexameric Hcp ring is acknowledged as a key effector carrier, the mechanism by which it recognizes and accommodates structurally diverse cargos remains unclear. Notably, gut-dominant Bacteroidota species encode at least five hcp genes within their T6SS loci, yet the biological significance of this multiplicity is unknown. Here, we show that Hcp2 and Hcp3 form an obligate heterohexamer essential for effector translocation. Cryo-EM structures reveal that the effector Bte1 undergoes substantial conformational rearrangements to fit into the rigid Hcp pore. Structural, evolutionary, and functional analyses demonstrate that lineage-specific Hcp2-Hcp3 complexes selectively associate with distinct effectors. This specificity is mediated primarily by hypervariable interfaces on Hcp3, which recognize a structurally conserved N-terminal module in effectors via a "lock-and-key" co-evolutionary mechanism. Our findings provide insights into effector-specific delivery in gut symbionts through combinatorial Hcp assembly, redefine the rules of T6SS cargo selection by highlighting conformational adaptability, and suggest potential engineering applications.

Source: Nature Communications

DOI: 10.1038/s41467-026-69309-z