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Structure of the Mycobacterium tuberculosis type VII secretion system

The growth or virulence of Mycobacterium tuberculosis bacilli depends on homologous type VII secretion systems, ESX-1, ESX-3 and ESX-5, which export a number of protein effectors across the special mycobacterial cell envelope to the bacterial surface and environment. PE and PPE proteins represent two large families of highly polymorphic proteins that are secreted by these ESX systems. Strikingly, at least some of these proteins are transported as heterodimers. Recently, we showed that these proteins require system-specific cytoplasmic chaperones, the EspG proteins, fortheir recognition and secretion (Daleke et al., J Biol Chem 2012). In this study by Korotkova et al., we solved the crystal structure of M. tuberculosisESX-5-secreted PE25–PPE41 heterodimerin complex with the cytoplasmic chaperoneEspG5. EspG5 represents a novel fold that is unrelated to previously characterized secretion chaperones. Functional analysis of the EspG5-binding region uncovered a hydrophobic patch on PPE41 that promotes dimer aggregation, and the chaperone effectively abolishes this process. We show that PPE41 contains a characteristic chaperone-binding sequence, the hh motif, which is highly conserved among ESX-1-, ESX-3- and ESX-5-specific PPE proteins. Disrupting the interaction between EspG5 and three different PPE target proteins by introducing different point mutations generally affected protein secretion. We further demonstrate that the EspG5 chaperone plays an important role in the ESX secretion mechanism by keeping aggregation-prone PE/PPE proteins in their soluble state.