GluCls

Glucocorticoid-induced leucine-rich small (GluCls) proteins constitute a conserved family of small, acid‑rich proteins that are widely distributed among bacterial and archaeal genomes. The term GluCls originates from the characteristic abundance of glutamic acid residues in the N‑terminal region, which gives the proteins a net negative charge and a propensity to interact with divalent cations and metal‑binding proteins. Members of the family typically contain 90–120 amino acids, a highly conserved coiled‑coil motif, and a C‑terminal acidic tail enriched in aspartate.

Functional studies suggest that GluCls act as regulatory adaptors in the cellular response to environmental stress. In several model organisms, deletion of glucl leads to altered tolerance to osmotic shock, while overexpression enhances growth under nutrient limitation. In vitro assays demonstrate that GluCls bind metal ions such as manganese and zinc with micromolar affinity, and that this binding modulates the activity of adjacent metalloproteases involved in protein quality control. Recent cryo‑electron microscopy structures of a GluCls–metalloprotease complex reveal that the GluCls coiled‑coil engages the protease’s regulatory domain, stabilizing an inactive conformation until the cell experiences a drop in metal ion concentrations.

The GluCls family is phylogenetically distinct from the RelA/SpoT homologs that produce the stringent response alarmone (p)ppGpp. Comparative genomic analysis indicates that GluCls genes co‑occur with operons encoding small regulatory RNAs and transcription factors implicated in carbon and nitrogen metabolism, suggesting a role in coordinating metabolic adaptation. Further investigations are needed to determine the precise biochemical mechanisms underlying GluCls function and their potential as targets for antimicrobial development.