Session: Current Topics in Biological Chemistry:

The phylum Actinobacteria comprise a diverse array of bacterial species, includes the major human pathogen Mycobacterium tuberculosis, the leading cause of global mortality due to infection. Actinobacterial Clp proteases perform important homeostatic and regulatory functions, and have emerged as novel antibacterial targets against drug-resistant M. tuberculosis. Clp proteases are composed of two distinct oligomeric components. An ATP-fueled unfoldase, such as ClpX, ClpA or ClpC, recognizes protein substrates and mechanically unfolds them using energy from ATP hydrolysis. The unfoldase translocates the resulting denatured polypeptides into ClpP, an associated barrel-shaped peptidase, for degradation. The interaction between Clp unfoldase and peptidase is stabilized by LGF/IGF loops present on the unfoldase, which dock into hydrophobic pockets on the surface of ClpP. ClpB, a close homolog of ClpA and ClpC, lack LGF/IGF loops and function independently as unfoldases. Through sequence analysis, we identified a novel, conserved group of actinobacterial ClpC paralogs with and without LGF/IGF loops. The novel ClpC paralogs lacking LGF/IGF loops presumably cannot associate with ClpP, and likely function as unfoldases rather than as proteolytic chaperones. We develop a set of bioinformatic methods to classify ClpC paralogs and characterize their specialized function based on their sequence characteristics. This workflow can be applied to other sets of paralogs in other clades, and can help identify specialized functions paralogs and define their importance to organism viability.

Karl R Schmitz PhD

Assistant Professor, University of Delaware

Appearances