Substrate Recognition and Cleavage-Site Preferences of Lon Protease.

The evolutionarily conserved AAA+ Lon protease plays a pivotal role in protein homeostasis by precisely remodeling the proteome and specifically removing unfolded, damaged, and surplus natively folded regulatory proteins. Proteolysis by Lon comprises the three fundamental stages of substrate recognition via specific amino acid sequence motifs (degrons), ATP-fueled substrate unfolding and translocation into a sequestered proteolytic chamber, and cleavage of the translocated polypeptide by the peptidase domain. Although a plethora of Lon substrates have been identified in several bacterial species, broadly applicable rules that govern recognition of numerous substrates, and hence the ability to de novo identify new Lon substrates and regulatory pathways, has lagged behind.