PDZ Domains Across the Microbial World: Molecular Link to the Proteases, Stress Response, and Protein Synthesis

The PSD-95/Dlg-A/ZO-1(PDZ)domain is highly expanded, diversified, andwell distributed acrossmetazoawhere it assemblesdiverse signaling components by virtue of interactionswith other proteins in a sequence-specificmanner. In contrast, in the microbialworld they are reported to be involved in protein quality control during stress response. The distribution, functions, and origins of PDZ domain-containing proteins in the prokaryotic organisms remain largely unexplored. We analyzed 7,852 PDZ domain-containing proteins in 1,474microbialgenomes inthis context. PDZdomain-containingproteins fromplanctomycetes,myxobacteria, andother eubacteria occupying terrestrial and aquatic niches are found to be inmultiple copieswithin their genomes.Over 93%of the 7,852 PDZ domain-containing proteins were classified into 12 families including six novel families based on additional structural and functional domains present in these proteins. The higher PDZ domain encoding capacity of the investigated organismswas observed to be associated with adaptation to the ecological niche where multicellular life might have originated and flourished. Predicted subcellular localization of PDZdomain-containing proteins and their genomic context argue in favor of crucial roles in translation and membrane remodeling during stress response. Based on rigorous sequence, structure, and phylogenetic analyses,we propose that the highly diverse PDZ domain of the uncharacterized Fe-S oxidoreductase superfamily, exclusively found in gladobacteria and several anaerobes and acetogens, might represent the most ancient form among all the existing PDZ domains.