Global atlas of predicted functional domains inLegionella pneumophilaDot/Icm translocated effectors

Abstract

Legionella pneumophila utilizes the Dot/Icm type IVB secretion system to deliver hundreds of effector proteins inside eukaryotic cells to ensure intracellular replication. Our understanding of the molecular functions of the largest pathogenic arsenal known to the bacterial world remains incomplete. By leveraging advancements in 3D protein structure prediction, we provide a comprehensive structural analysis of 368 L. pneumophila effectors, representing a global atlas of predicted functional domains summarized in a database (https://pathogens3d.org/legionella-pneumophila). Our analysis identified 157 types of diverse functional domains in 287 effectors, including 159 effectors with no prior functional annotations. Furthermore, we identified 35 unique domains in 30 effector models that have no similarity with experimentally structurally characterized proteins, thus, hinting at novel functionalities. Using this analysis, we demonstrate the activity of thirteen domains, including three unique folds, predicted in L. pneumophila effectors to cause growth defects in the Saccharomyces cerevisiae model system. This illustrates an emerging strategy of exploring synergies between predictions and targeted experimental approaches in elucidating novel effector activities involved in infection.

A survey of ADP-ribosyltransferase families in the pathogenicLegionella

“…Although the predicted effector functions remain to be validated, these novel ART-like families present attractive candidates for experimental studies into mechanisms of pathogenicity due to their likely crucial roles in the pathogen's survival. While this manuscript was being finalised, a thorough study presented a detailed survey of structural domains in all the effectors of L. pneumophila (Patel et al, 2024). While our study addresses only ART-like proteins, it is complementary to work of Patel et al because we surveyed 41 species instead of one and did not limit the exploration to effectors.…”