Mikrobiologie
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Gene regulation

Regulatory signal transduction systems link extra- and intracellular stimuli with cellular responses. The success of an organism depends decisively on the optimal adaptation to the prevailing conditions. On the one hand, the existing regulatory mechanisms play a role when it comes to natural fluctuations within the ecological niche. On the other hand, the flexibility of the regulatory networks is also important, especially when it comes to the conquest of new habitats with a changed range of fluctuation. Predominately, bacteria rely on two major types of regulation systems when it comes to transcriptional control. The first, are so called one-component system, which combine input and output domains within a single protein. Second, in two-component signal-transduction input and output are separated on at least two distinct proteins - a histidine kinase and a response regulator - in turn enabling more complex regulatory circuits. Whereas the number of outputs is limited and most often results in transcriptional control a sheer unlimited amount of signal can be recognized by an arsenal of input domains.
In my group we are interested to identify new transcriptional control regimes towards non-canonical amino acids such as fructose lysine and to understand these systems at the molecular level.

 

Translational stress response

Synthesis of polyproline proteins leads to translation arrest. To overcome this ribosome stalling effect, bacteria depend on a specialized translation elongation factor P (EF-P), being orthologous and functionally identical to eukaryotic/archaeal elongation factor e/aIF-5A (recently renamed ‘EF5’). EF-P binds to the stalled ribosome between the peptidyl-tRNA binding and tRNA-exiting sites, and stimulates peptidyl transferase activity, thus allowing translation to resume. In their active form, both EF-P and e/aIF-5A are post-translationally modified at a positively charged residue, which protrudes toward the peptidyl transferase center when bound to the ribosome. While archaeal and eukaryotic IF-5A strictly depend on (deoxy-) hypusination of a conserved lysine, bacteria have evolved diverse analogous modification strategies to activate EF-P. In Escherichia coli and Salmonella enterica a lysine is extended by β-lysinylation and subsequently hydroxylated, whereas in Pseudomonas aeruginosa and Shewanella oneidensis an arginine in the equivalent position is rhamnosylated. Inactivation of EF-P, or the corresponding modification systems, reduces not only bacterial fitness, but also impairs virulence.
In my group we are interested to understand why nature has evolved such a chemical diversity of post-translational EF-P modification systems and are further investigating the molecular determinants for EF-P dependent ribosome rescue.

 

Post-translational modifications

Post-translational modifications (PTM) are the evolutionary solution to challenge and extend the boundaries of genetically predetermined proteomic diversity. Since PTMs are highly dynamic, they also hold an enormous regulatory potential. It is therefore not surprising that out of the 20 proteinogenic amino acids, 15 can be post-translationally modified. In higher eukaryotes, up to 5 % of the total genome can be dedicated to such modifiers. Although bacteria are often considered to be simple organisms with very basal cellular regulation, their proteome is also subject to substantial directed post-translational changes. In general, PTMs can be classified into two major categories: The first comprises the alteration of the primary sequence by non-ribosomal formation of a new peptide bond or conversely its cleavage by limited proteolysis. The second category includes the modification of a side chain by covalent addition of a chemical group, which itself can be highly diverse. Accordingly, the corresponding catalogue of PTMs is large and includes but is not limited to methylation, acylation, phosphorylation as well as glycosylation.
In my group we are interested in novel and unusual bacterial glycoproteins such as EF-P of pseudomonads. We also aim to understand the regulatory potential, lying in the competition of diverse acylations for the same acceptor lysine.