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Research interests

Type 4 Secretion Systems (T4SS)

These systems are present in both Gram-negative and Gram-positive bacteria. They form multi-megaDalton machines embedded in membranes and are responsible for the secretion of both proteins and nucleic acid substrates. They play major roles in pathogenicity of, for example, Helicobacter pylori, the causative agent of ulcers. They also mediate transfer of plasmid DNAs during conjugation, a process that leads to the spread of antibiotics resistance genes. T4S systems are composed of 12 proteins named VirB1-11 and VirD4 that assemble into a formidable nanomachine of more than 3 megaDalton in size and spanning the two membranes of Gram-negative bacteria.

References

Download a recent review and our landmark papers in Nature and Science. Trokter M, Felisberto-Rodrigues C, Christie PJ and Waksman G (2014). Recent advances in the structural and molecular biology of type IV secretion systems. Curr Opin Struct Biol. 2014 Aug;27:16-23. doi: 10.1016/j.sbi.2014.02.006. Epub 2014 Apr 5.

Low HH, Gubellini F, Rivera-Calzada A, Braun N, Connery S, Dujeancourt A, Lu F, Redzej A, Fronzes R, Orlova EV, Waksman G (2014). Structure of a type IV secretion system. Nature. 2014 Apr 24;508(7497):550-3. doi: 10.1038/nature13081. Epub 2014 Mar 9

Wallden K, Rivera-Calzada A, G. Waksman (2010). Type IV secretion systems: versatility and diversity in function. Cell Microbiol. Sep 1;12(9):1203-12. Review

Chandran, R. Fronzes, S. Duquerroy, N. Cronin, J. Navaza, and G. Waksman (2009). Crystal structure of the outer membrane complex of a type IV secretion system. Nature. 462:1011-1015

R. Fronzes, E. Schaefer, H. Saibil, E. Orlova and G. Waksman (2009). Structure of type IV secretion core complex. Science. 323:266-268

Pilus biogenesis

Bacterial pili are hair-like surface-exposed organelles. They are responsible for recognition of and attachment to the host and thus, are also crucial virulence factors. Pili are polymer of protein subunits, the assembly of which require accessory proteins. There are two biogenesis pathways for the production of pili in Gram-negative bacteria: the chaperone-usher pathway and the type IV pilus biogenesis pathway - not to be confused with T4S systems! We are engaged in research on both, but have made most progress on the former. Chaperone-usher (CU) pili have clear relevance in the pathogenicity of uropathogenic Escherichia coli, where CU pili mediate bacterial tropism to the bladder to cause cystitis or to the kidney to cause pyolenephritis. CU pili require two accessory proteins for biogenesis: a chaperone that stabilises pilus subunits and ferries them to an assembly platform, the usher, the second accessory protein required in this system. The usher is an extraordinary molecular nanomachine embedded in the outer membrane. It drives subunit recruitment, polymerisation and secretion. All in one protein

References

Please click on the links below to download recent reviews and also our landmark papers in Nature, Science, and Cell.

Hospenthal MK, Redzej A, Dodson K, Ukleja M, Frenz B, Rodrigues C, Hultgren SJ, DiMaio F, Egelman EH, Waksman G (2016) Structure of a Chaperone-Usher Pilus Reveals the Molecular Basis of Rod Uncoiling. Cell 164, 269–278

Allen WJ, Phan G, Waksman G (2012) Pilus biogenesis at the outer membrane of Gram-negative bacterial pathogens. Curr Opin Struct Biol. Aug;22(4):500-6. doi: 10.1016/j.sbi.2012.02.001. Epub 2012 Mar 6

Busch A, Waksman G (2012) Chaperone-usher pathways: diversity and pilus assembly mechanism. Philos Trans R Soc Lond B Biol Sci. Apr 19;367(1592):1112-22. doi: 10.1098/rstb.2011.0206.

Geibel S, Procko E, Hultgren SJ, Baker D, Waksman G (2013) Structural and energetic basis of folded-protein transport by the FimD usher. Nature. Apr 11;496(7444):243-6. doi: 10.1038/nature12007.

G. Phan, H. Remaut, T.Wang, W. Allen, K. Pirker, A. Lebedev, N. Henderson, S. Geibel, E. Volkan, J. Yan, M. Kunze, J. Pinkner, B. Ford, C. Kay, H. Li, S. Hultgren, D. Thanassi, and Waksman G (2011). Crystal structure of the FimD usher bound to its cognate FimC:FimH substrate. Nature. 474:49-53.

K.W. Dodson, J.S. Pinkner, T. Rose, G. Magnusson, S.J. Hultgren, and Waksman G (2001). Structural Basis of Tropism of Pyelonephritic /E. coli/ for the Human Kidney. Cell. 105:733–743.

F.G. Sauer, K. Fütterer, J.S. Pinkner, K.W. Dodson, S.J. Hultgren, and Waksman G (1999). Structural basis of chaperone function and pilus biogenesis. Science. 285:1058-1061

Professor Gabriel Waksman