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Résumé

Bacteriophages of the myoviridae family, R-type pyocin, Photorhabus virulence cassette (PVC), Serratia antifeeding prophage (Afp) and type 6 secretion system (T6SS) form a class of contractile injection systems that share common structural and functional components. The baseplate is a complex macromolecular structure that can change conformation. The tail is a rigid tube surrounded by a contractile sheath. They efficiently translocate genetic material (bacteriophages), deliver toxins into the external milieu or neighboring cells (PVC, Afp and T6SS) and efficiently kill competitor bacteria by depolarizing the membrane potential (Pyocin). The host range of bacteriophages or target spectrum of R-type pyocins, PVC, Afps is determined by filamentous tail fibers and more bulky tailspikes (TSP) that emanate from the baseplate. The recently discovered bacteriophage CBA120 encodes six putative host attachment proteins, of which four (named TSP1- TSP4) show some sequence similarity to known tailspikes. Despite four different proteins, CBA120 was found to be highly specific toward one host, namely E. coli O157:H7, a frequent contaminant of ground beef and a well-known human pathogen. In this work the crystallographic structure of TSP2, TSP3 and TSP4 are presented. In addition, functional assays suggest that CBA120 has at least three potential hosts. The structure of TSP1 was solved elsewhere but no activity was found towards E. coli O157:H7 or any other host. To better understand how the four TSP bind the phage particle, the TSP complex was formed in vitro and a new complex formation pathway was suggested. In addition to the CBA120, crystal structures of two TSP from Acinetobacter baumannii specific phages were solved. Acinetobacter baumannii is a highly drug resistant “flesh-eating” bacterium. Studies conducted with R-type pyocin show that its host specificity can be manipulated by changing the host attachment fiber. It was also shown that the native fiber protein could be exchanged for TSP proteins. In order to be incorporated in the pyocin particle, a new TSP can be fused to a 164 residue long N-terminal domain of the native fiber. This fragment is critical for maintaining the integrity of the baseplate and for transmitting the target surface binding signal to it. To obtain the structure of this fragment, we created a fusion of this domain with a well-crystallizable TSP. Several other proteins of the pyocin baseplate were cloned, expressed and purified. The result of these experiments was the determination of the crystal structure of the proteolytically stable fragment of PA0618, the largest protein of the pyocin baseplate. PA0618 is orthologous to T4 gp6, which is responsible of circularization of the baseplate. Taken together the structures of five previously unknown TSP and the proteolytically stable fragment of PA0618 were determined. The acquired structural information will help to better understand the relationship of peptide sequence, structure and function, in particular, the interaction of TSP and fiber proteins with polysaccharides that decorate the bacterial surface. Furthermore, all crystal structures reported here were determined by de novo phasing, and this structural information will further improve the ability to predict protein structure. Thanks to the enzymatic activity of the TSP proteins and their ability to specifically target bacterial cells, these proteins can be used in antimicrobial applications.

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