Deep mutational scanning of EccD3 reveals the molecular basis of its essentiality in the mycobacterium ESX secretion system
Trinidad, D. D.; Macdonald, C. B.; Rosenberg, O. S.; Fraser, J. S.; Coyote-Maestas, W.
Show abstract
Tuberculosis remains the deadliest infectious disease in the world and requires novel therapeutic targets. The ESX-3 secretion system, which is essential for iron and zinc homeostasis and thus M. tuberculosis survival, is a promising target. In this study, we perform a deep mutational scan on the ESX-3 core protein EccD3 in the model organism M. smegmatis. We systematically investigated the functional roles of 145 residues across the soluble ubiquitin-like domain, the conformationally distinct flexible linker, and selected transmembrane helices of EccD3. Our data combined with structural comparisons to ESX-5 complexes support a model where EccD3 stabilizes the complex, with the hinge motif within the linker being particularly sensitive to disruption. Our study is the first deep mutational scan in mycobacteria, which could help guide drug development toward novel treatment of tuberculosis. This study underscores the importance of context-specific mutational analyses for discovering essential protein interactions within mycobacterial systems.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Periplasm homeostatic regulation maintains spatial constraints essential for cell envelope processes and cell viability 95%
- Resolving phylogenetic and biochemical barriers to functional expression of heterologous iron-sulphur cluster enzymes 95%
- Staphylococcus aureus FtsZ and PBP4 bind to the conformationally dynamic N-terminal domain of GpsB 95%
Similar papers in this journal
- Hybrid Exb/Mot stators require substitutions distant from the chimeric pore to power flagellar rotation 95%
- The vibriophage-encoded inhibitor OrbA abrogates BREX-mediated defense through the ATPase BrxC 94%
- Genome wide functional screen for calcium transients in E. coli identifies decreased membrane potential adaptation to persistent DNA damage 93%
Similar papers in this journal
- Disulfide bonds are required for cell division, cell envelope biogenesis and antibiotic resistance proteins in mycobacteria 96%
- A new role for lipoproteins LpqZ and FecB in orchestrating mycobacterial cell envelope biogenesis 96%
- AcrIF11 is a potent CRISPR-specific ADP-ribosyltransferase encoded by phage and plasmid 96%
Similar papers in this journal
- Horizontal gene transfer in the human and skin commensal Malassezia: a bacterially-derived flavohemoglobin is required for NO resistance and host interaction 95%
- Fluoride triggers lysis in Streptococcus mutans by inhibition of Clp protease complex leading to an unabated competence cascade 95%
- DprA recruits ComM to facilitate recombination during natural transformation in Gram-negative bacteria 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.