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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 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 (Desvaux et al. 2004). 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). This conclusion has been confirmed (van Ulsen 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.Tthe translocation process of autotransporters and the structural motifs that are unique to this class of proteins have been reviewed (Kiessling et al. 2019).

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)

References associated with 1.B.40 family:

Ackermann, N., M. Tiller, G. Anding, A. Roggenkamp, and J. Heesemann. (2008). Contribution of trimeric autotransporter C-terminal domains of oligomeric coiled-coil adhesin (Oca) family members YadA, UspA1, EibA, and Hia to translocation of the YadA passenger domain and virulence of Yersinia enterocolitica. J. Bacteriol. 190: 5031-5043. 18487327
Aoki, E., D. Sato, K. Fujiwara, and M. Ikeguchi. (2017). Electrostatic Repulsion between Unique Arginine Residues is Essential for the Efficient In Vitro Assembly of the Transmembrane Domain of a Trimeric Autotransporter. Biochemistry. [Epub: Ahead of Print] 28357859
Bentancor, L.V., A. Camacho-Peiro, C. Bozkurt-Guzel, G.B. Pier, and T. Maira-Litrán. (2012). Identification of Ata, a multifunctional trimeric autotransporter of Acinetobacter baumannii. J. Bacteriol. 194: 3950-3960. 22609912
Desvaux, M., N.J. Parham, and I.R. Henderson. (2004). Type V protein secretion: simplicity gone awry? Curr Issues Mol Biol 6: 111-124. 15119822
El Tahir, Y. and M. Skurnik. (2001). YadA, the multifaceted Yersinia adhesin. Int. J. Med. Microbiol. 291: 209-218. 11554561
Forman, S., C.R. Wulff, T. Myers-Morales, C. Cowan, R.D. Perry, and S.C. Straley. (2008). yadBC of Yersinia pestis, a new virulence determinant for bubonic plague. Infect. Immun. 76: 578-587. 18025093
Grosskinsky, U., M. Schütz, M. Fritz, Y. Schmid, M.C. Lamparter, P. Szczesny, A.N. Lupas, I.B. Autenrieth, and D. Linke. (2007). A conserved glycine residue of trimeric autotransporter domains plays a key role in Yersinia adhesin A autotransport. J. Bacteriol. 189(24):9011-9019. 17921300
Hartmann, M.D., I. Grin, S. Dunin-Horkawicz, S. Deiss, D. Linke, A.N. Lupas, and B. Hernandez Alvarez. (2012). Complete fiber structures of complex trimeric autotransporter adhesins conserved in enterobacteria. Proc. Natl. Acad. Sci. USA 109: 20907-20912. 23213248
Jiang, X., T. Ruiz, and K.P. Mintz. (2011). The Extended Signal Peptide of the Trimeric Autotransporter EmaA of Aggregatibacter actinomycetemcomitans Modulates Secretion. J. Bacteriol. 193: 6983-6994. 22001514
Kiessling, A.R., A. Malik, and A. Goldman. (2019). Recent advances in the understanding of trimeric autotransporter adhesins. Med Microbiol Immunol. [Epub: Ahead of Print] 31865405
Leo, J.C., I. Grin, and D. Linke. (2012). Type V secretion: mechanism(s) of autotransport through the bacterial outer membrane. Philos Trans R Soc Lond B Biol Sci 367: 1088-1101. 22411980
Lu, Q., Y. Xu, Q. Yao, M. Niu, and F. Shao. (2015). A polar-localized iron-binding protein determines the polar targeting of Burkholderia BimA autotransporter and actin tail formation. Cell Microbiol 17: 408-424. 25293534
Meng, G., N.K. Surana, J.W. St Geme, 3rd, and G. Waksman. (2006). Structure of the outer membrane translocator domain of the Haemophilus influenzae Hia trimeric autotransporter. EMBO. J. 25: 2297-2304. 16688217
Peterson, J.H., S. Hussain, and H.D. Bernstein. (2018). Identification of a novel post-insertion step in the assembly of a bacterial outer membrane protein. Mol. Microbiol. 110: 143-159. 30107065
Roggenkamp, A., N. Ackermann, C.A. Jacobi, K. Truelzsch, H. Hoffmann, and J. Heesemann. (2003). Molecular analysis of transport and oligomerization of the Yersinia enterocolitica adhesin YadA. J. Bacteriol. 185: 3735-3744. 12813066
Scarselli M., D. Serruto, P. Montanari, B. Capecchi, J. Adu-Bobie, D. Veggi, R. Rappuoli, M. Pizza, B. Aricò. (2006). Neisseria meningitidis NhhA is a multifunctional trimeric autotransporter adhesin. Mol. Microbiol. 61: 631-644. 16803596
Serruto, D., T. Spadafina, M. Scarselli, S. Bambini, M. Comanducci, S. Höhle, M. Kilian, E. Veiga, P. Cossart, M.R. Oggioni, S. Savino, I. Ferlenghi, A.R. Taddei, R. Rappuoli, M. Pizza, V. Masignani, and B. Aricò. (2009). HadA is an atypical new multifunctional trimeric coiled-coil adhesin of Haemophilus influenzae biogroup aegyptius, which promotes entry into host cells. Cell Microbiol 11: 1044-1063. 19290916
Sheets, A.J., S.A. Grass, S.E. Miller, and J.W. St Geme, 3rd. (2008). Identification of a novel trimeric autotransporter adhesin in the cryptic genospecies of Haemophilus. J. Bacteriol. 190: 4313-4320. 18424521
Tang, G., T. Ruiz, R. Barrantes-Reynolds, and K.P. Mintz. (2007). Molecular heterogeneity of EmaA, an oligomeric autotransporter adhesin of Aggregatibacter (Actinobacillus) actinomycetemcomitans. Microbiology. 153: 2447-2457. 17660409
Valle, J., A.N. Mabbett, G.C. Ulett, A. Toledo-Arana, K. Wecker, M. Totsika, M.A. Schembri, J.M. Ghigo, and C. Beloin. (2008). UpaG, a new member of the trimeric autotransporter family of adhesins in uropathogenic Escherichia coli. J. Bacteriol. 190: 4147-4161. 18424525
van Ulsen, P., K.M. Zinner, W.S.P. Jong, and J. Luirink. (2018). On display: autotransporter secretion and application. FEMS Microbiol. Lett. 365:. 30085010