Escherichia coli DegP: a Structure-Driven Functional Model

Structural biology has been extremely successful in providing functional insights for a large number of proteins and macromolecular assemblies, but in some cases, the structure has contributed a three-dimensional (3D) framework to interpret years of accumulated biochemical and genetic knowledge. In these particular systems, structural information has allowed us to learn things that would have been difficult to learn with other techniques. The periplasmic Escherichia coli DegP protease/chaperone exemplifies this scenario very well. This protein was initially identified in the 1980s (23, 24, 37, 38), and over more than two decades, several groups characterized its activities (2, 12, 16, 27). However, a comprehensive 3D functional model did not become apparent until the first DegP X-ray structure was revealed in 2002 (20). Following the discovery of this remarkable structure, a number of groups concentrated on testing the essentials of the functional model proposed from the crystal structure. Interestingly, this functional model was rewritten recently, after the structures of DegP in two additional oligomeric forms were resolved (13, 22). Current research efforts are now concentrated on probing the new functional model and also on answering new, interesting questions posed by these structures. Therefore, DegP provides an excellent example for the structure-driven study of protein function. This minireview aims to summarize how the functional model for DegP protein has evolved as the structures of the different oligomeric forms of the protein have been elucidated. E. coli DegP (also called HtrA or protease Do) is an important periplasmic protein with the unusual property of functioning both as a protease and as a chaperone (36). Unlike the cytoplasmic compartment, the periplasm lacks ATP and does not support the function of large protein machines powered by this molecule. However, in this cellular compartment, DegP can still degrade and refold misfolded proteins in an ATPindependent manner (2). Although DegP is not an essential protein, its activity is required for bacterial survival at high temperatures (34) and under harsh environmental conditions. Consequently, its expression is upregulated by both the Cpx and E protein quality control pathways under conditions of protein-folding stress (3, 29). DegP homologs have been isolated from a variety of species, including gram-negative and -positive bacteria, plants, and mammals. All these proteins constitute the HtrA family of proteases (2). In bacteria, members of this family are key players mainly in protein quality control in the periplasmic space. In eukaryotic cells, these proteins are involved in functions as diverse as the regulation of apoptosis (1, 4, 9) and the delay of the aggregation process of intracellular amyloid peptides (19). HtrA proteins usually contain a protease domain and at least one C-terminal PDZ domain. In some cases, members of this family of proteins also include additional domains, such as transmembrane regions, located usually at the N terminus. Specifically, in E. coli, DegP, DegQ, and DegS compose the HtrA family. There is a high degree of homology among these three proteins, particularly in the protease domain. However, the number of PDZ domains is variable. DegP and DegQ contain two PDZ domains, whereas DegS contains only one (16).