1.B.40 The Autotransporter-2 (AT-2) Family
The Yersinia adhesin -A (YadA) of Y. enterocolitica is a trimeric autotransporter adhesion with three major domains: an N-terminal head mediating adherence to host cells, a stalk involved in serum resistance, and a C-terminal anchor that forms a membrane pore and is responsible for the autotransport function. The anchor contains a glycine residue, nearly invariant throughout trimeric autotransporter adhesins, that faces the pore lumen: This conserved glycine residue affects both the export and the stability of YadA, and consequently some of its putative functions in pathogenesis (Reggenkamp et al., 2003; Grosskinsky et al., 2007). YadA mediates attachment to the surfaces of host cells and protects the bacteria against complement and the bactericidal activities of defensins (El Tahir and Skurnik, 2001). This protein is the prototype of a new family of bacterial adhesins that form oligomeric lollypop-like structures anchored in the outer membrane by their C-termini. The AT-2 family has also been called the oligomeric coiled-coil adhesin (Oca) family. Leo et al. (2012) review these and other (putative) autotransporters. Several reports suggest that AT2 proteins may not alone translocate their passenger domains to the outer surface of the outer membrane, but instead may use the β-barrel assembly machinery (BAM complex) to accomplish this task (Peterson et al. 2018).
The C-terminal region (residues 355-422) of YadA consists of four amphipathic β-strands and is necessary and sufficient for the outer membrane insertion of this trimeric adhesin. It is also responsible for oligomerization. The linker region (residues 331-369) is required for outer membrane translocation of the N-terminal passenger domain. In these functional respects, YadA resembles the autotransporters of the AT family (TC #1.B.12). The C-terminal translator domains of AT-2 Oca proteins of different origin are efficient translocators of the YadA passenger-domain. Further, the cognate TLD of YadA is essential for bacterial survival in human serum and mouse virulence (Ackermann et al., 2008).
YadA shows no sequence similarity with AT proteins in the C-terminal AT domain. Moreover, while the C-terminal porin regions of AT family members are of about 250 residues, exhibit about 14 transmembrane β-strands and form large oligomers (8-10 mers), the C-terminal pore-forming anchors of AT-2 family members are only of about 70 residues, have just 4 transmembrane β-strands, and form trimers. These facts suggest that the pore-forming units that translocate their N-terminal passenger domains evolved independently. They therefore belong to distinct families.
Hundreds of homologues of YadA have been sequenced. They have been termed invasins, immunoglobulin binding proteins, serum resistance proteins and hemagglutinins. They are encoded in the genomes of a wide variety of Gram-negative bacteria and their phage. They vary in size (340- >4000 aas) with multiple (2-8) repeat domains of about 150 residues, and these may consist of smaller repeat units.
NhhA, Neisseria hia/hsf homologue, or GNA0992, is an oligomeric outer membrane protein of Neisseria meningitidis, included in the family of trimeric autotransporter adhesins. The last 72 C-terminal residues allow trimerization and localization of the N-terminal protein domain to the bacterial surface. E. coli strains expressing NhhA were able to adhere to epithelial cells. NhhA is a multifunctional adhesin, able to promote the bacterial adhesion to host cells and extracellular matrix components (Scarselli et al., 2006).
Haemagglutinins of B. xenovorans (1.B.40.1.2) contain repeat sequences that are homologous to repeat sequences in AT1 proteins and the toxins of TC# 1.C.11.1.4, 1.C.57.3.4 and 1.C.75.1.1, members of the RTX superfamily, as well as other toxins in these families, and TolA (2.C.1.2.1). These repeat sequences probably mediate protein-protein interacts and comprise parts of toxins.
The reaction catalyzed by YadA is:
N-terminal substrate domain (periplasm) → N-terminal substrate domain (outer surface of outer membrane)