A Common Structural Motif in the Binding of Virulence Factors to Bacterial Secretion Chaperones

Abstract

Salmonella invasion protein A (SipA) is translocated into host cells by a type III secretion system (T3SS) and comprises two regions: one domain binds its cognate type III secretion chaperone, InvB, in the bacterium to facilitate translocation, while a second domain functions in the host cell, contributing to bacterial uptake by polymerizing actin. We present here the crystal structures of the SipA chaperone binding domain (CBD) alone and in complex with InvB. The SipA CBD is found to consist of a nonglobular polypeptide as well as a large globular domain, both of which are necessary for binding to InvB. We also identify a structural motif that may direct virulence factors to their cognate chaperones in a diverse range of pathogenic bacteria. Disruption of this structural motif leads to a destabilization of several chaperone-substrate complexes from different species, as well as an impairment of secretion in Salmonella.

Yersinia pestis YopD 150–287 fragment is partially unfolded in the native state

“…The hypothesis is supported by crystal structures of the Sip-SptP (1-158) complex, which shows a partially unfolded effector [11]. Similar observations have been confirmed in other complexes of effector fragments and chaperones, suggesting that the effector fragments prefer extended conformations when binding to chaperones [12][13][14]. In agreement with the previous data, it has been shown recently that the binding of the SycN-YscB complex to the secretion substrate YopN is through an extended conformation with some secondary but no tertiary structure [15].…”

Hierarchical Delivery of an Essential Host Colonization Factor in Enteropathogenic Escherichia coli

“…A study by Lilic et al (26) suggests that a number of type III effectors have a conserved structural ␤-fold that type III secretion chaperones interact with. This does not appear to be the case for all of the EPEC type III effectors that interact with CesT, since the presumed structural ␤-folds are not in a proper spatial context for dimeric CesT binding.…”

Secretion and translocation signals and DspB/F-binding domains in the type III effector DspA/E of Erwinia amylovora

“…delivery outside the bacterial cell) or translocation (i.e. delivery into host cells) in animal bacterial pathogens is accomplished in part by a short N-terminal secretion signal often located within the first 15-20 amino acids of type III (T3)-secreted proteins (Lilic et al, 2006;Lloyd et al, 2002;Sorg et al, 2005). The exact means by which this N-terminal signal targets proteins for secretion and translocation is unclear.…”

“…For example, in Salmonella spp., the absence of the chaperone for a secreted protein can preclude its secretion unless the CBD is also absent (Ehrbar et al, 2006;Lilic et al, 2006). If the CBD of an effector is deleted but the N-terminal secretion signal remains, secretion through the T3SS can be thwarted and the effector can be rerouted to the flagellar secretion apparatus, indicating that the chaperone and its CBD confer some specificity for T3 secretion on effectors (Lee & Galán, 2004;Lilic et al, 2006). However, this CBDdetermined specificity does not exist in all bacterial systems.…”