Structure and activation of a heteromeric protease complex.

Abstract

New drug therapies are needed for treating Mycobacteria tuberculosis infections because strains with multiple drug resistances have arisen that tolerate almost all existing antibiotics (1). Regulated protein degradation is a universal process found in all kingdoms of life and is crucial for development, virulence, and pathogenicity in many bacteria, including M. tuberculosis (2⇓–4). Regulated degradation is principally carried out by energy-dependent proteases, such as the caseinolytic peptidase P (ClpP)-dependent family of proteases (5). These proteases consist of two oligomeric components: an ATP-consuming complex that is selective for substrate engagement, unfolding, and translocation (e.g., ClpX, ClpA, ClpC), and a chambered peptidase (ClpP) with sequestered active site serines that catalyze peptide bond hydrolysis. In many bacteria, a single clpP gene encodes a single protein that assembles into a homomeric tetradecamer; however, M. tuberculosis has two ClpP orthologs that are active only in a heteromeric ClpP1P2 complex (6). Other cases of multiple ClpP paralogs have been found in the genomes of both prokaryotic and eukaryotic organisms (7), but there has been limited characterization of these heteromeric complexes at the atomic scale. In PNAS, Schmitz et al. report the crystal structure of the M. tuberculosis ClpP1P2 complex, revealing the first high-resolution structure of a heteromeric ClpP complex and demonstrating how binding partners can dramatically affect ClpP activity through allosteric changes (8). The ClpP peptidase chamber can be envisioned as a static box that simply waits for delivery of unfolded substrates by the attendant ATPase and will digest whatever is passed to it (Fig. 1). However, recent biochemical and structural studies reveal a richer communication … [↵][1]1To whom correspondence should be addressed. Email: pchien{at}biochem.umass.edu. [1]: #xref-corresp-1-1