Trends in Microbiology
Volume 16, Issue 8, August 2008, Pages 370-379
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Review
Common themes and variations in serine protease autotransporters

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The serine protease autotransporters of the Enterobacteriaceae (SPATEs) represent a group of large-sized, multi-domain exoproteins found only in pathogenic enteric bacteria. These proteins contain a highly conserved channel-forming C-terminal domain, which functions together with YaeT/Omp85 to facilitate secretion of the passenger domain to the cell surface. The C-terminal domain also mediates autoproteolytic cleavage, which releases the passenger from the bacterial cell. The passenger folds into a characteristic parallel β-helical stalk-like structure with an N-terminal globular domain that performs serine proteolytic activity. Here, we review and discuss recent findings that have led to a better understanding of these unique features in this virulence protein family, including their biogenesis, structural architecture, sequence variation, sub-grouping, evolution and biochemical function.

Section snippets

A family of proteolytic virulence proteins secreted by the autotransporter pathway

Multiple pathways for protein secretion have been described in Gram-negative bacteria [1]. The serine protease autotransporters of the Enterobacteriaceae (SPATEs) constitute a group of exoproteins secreted by pathogenic enteric bacteria of the γ-proteobacteria through the autotransporter (AT) or type V pathway. The majority of proteins secreted by this pathway are virulence factors implicated in bacterial pathogenesis 2, 3. The secreted component and the secretion apparatus of an AT system are

Biogenesis of functionally active SPATE proteins

The Sec-dependent inner membrane (IM) translocation of a SPATE relies on its extended N-terminal signal peptide (SP), which ranges from 48 to 59 amino acid residues (Table 1). The extension contains a conserved sequence motif (Figure 1a) that is unique to several AT and two-partner secretion (TPS) proteins originated from the β- or γ-proteobacteria [10]. It remains controversial whether the extended SP mediates a co- or post-translational secretion of the SPATE proprotein [11] and whether the

Structural arrangement of the passenger domain: the code of virulence

Although equipped with the ability to perform different functions, SPATE passenger domains display a similar architecture, rich in β-strands, and are predicted to fold into a parallel β-helical structure, a fold verified by the crystal structure of the SPATE protein Hbp [31]. In agreement with the two solved crystal structures of Pertactin (Prn) from B. pertussis[32] and vacuolating toxin VacA from Helicobacter pylori[33], which are both non-SPATE ATs, the Hbp passenger comprises a ‘stalk’

Translocator domain: the means of delivery

Biochemical studies on the translocators of two SPATEs, Tsh and EspP, indicate that each exists as a monomeric unit in vitro15, 38. The recent crystal structure of the EspP translocator domain confirms the conventional AT status of the SPATEs [19]. Like the previously crystallized translocator domain of conventional AT NalP from Neisseria[26], the EspP translocator forms a 12-strand β-barrel that is connected to the α-helical linker at its N terminus. Unlike NalP, the linker of which plugs the

Variations among SPATEs

New SPATEs were discovered recently in Citrobacter rodentium and the E. coli strains E22, B7A and F11 (Y.T. Yen and C. Stathopoulos, unpublished). Deviations from key characteristics of SPATEs have been noted in new members. Recently, a SPATE homolog named RpeA from rabbit enteropathogenic E. coli was found to have no cleavage site in the linker region [41], probably making this putative SPATE the first member without a C-terminal processing site.

Within the bona fide SPATE members, the most

Evolution of the SPATEs

A study by Yen et al.[42] suggested that all members of the AT family have arisen through speciation. Broadly speaking, this is true with only limited examples of horizontal gene transfer occurring. One example of horizontal gene transfer is the existence of the gene encoding a SPATE protein (Boa) within Salmonella bongori. The absence of SPATEs from all other Salmonella sp. and the close homology of Boa to the E. coli SPATEs indicate strongly that this has been acquired through horizontal gene

SPATE-like serine protease ATs outside the Enterobacteriaceae family

Several ATs outside the Enterobacteriaceae family, including the well characterized IgA proteases from Neisseria gonorrhoeae[29] and Hap from nontypeable Haemophilus influenzae[36], in addition to a new member from Campylobacter concisus, also contain the serine protease motif (Table 2). Most of the motifs present in the passenger domains of SPATEs are found in the passenger domains of non-Enterobacteriaceae serine protease ATs, suggestive of functional commonality shared by these two groups.

Concluding remarks and future perspectives

SPATEs are multifunctional virulence-associated proteins of the AT family that have gained increasing attention owing to their involvement in numerous enteric diseases 2, 9. Currently, >20 SPATEs have been identified. A summary of what is known currently about SPATEs is provided in Box 1. Although functional, structural and secretion studies have provided insights into the properties of several SPATE proteins 2, 9, many members have not yet been characterized and several questions about this

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