Host-Pathogen Interactions via Ubiquitination Pathways

Abstract

Ankyrin B (AnkB) is a bacterial protein that plays an essential role in the intracellular proliferation of Legionella pneumophila, the causative agent of Legionnaires’ disease. It collects proteins to target for degradation into free amino acids, generating a source of carbon and energy, and preventing a starvation response. AnkB contains two eukaryotic-like domains, the combination of which have never been found in the same eukaryotic protein. The N-terminal F-box domain allows mimicry of host F-box proteins for interaction with the host's ubiquitination pathway via Skp1 of the SCF (Skp1-Cullin-F-box) E3 ubiquitin ligase complex. The C-terminal ankyrin repeats allow AnkB to selectively bind targets for degradation. Here, we report the crystal structure of full length AnkB in complex with host Skp1. We found that AnkB contains an enlarged the substrate-binding site with three ankyrin repeats rather than the two expected based on its sequence. Structural analyses and mutational studies have identified key residues responsible for decorating the Legionella-containing vacuole with ubiquitin and for the replication of the pathogen during infection.Our study provides the first structural insights into the structural mimicry that allows the bacterial virulence factor, AnkB, to associate with the host ubiquitination complex and select substrates.