Dokument

Summary:
Histidine-aspartate signaling systems are used by bacteria, archaea and eukarya to integrate stimuli over time and space generating coordinated, fine-tuned cellular responses. A hallmark feature is the high modularity of the signaling protein modules which can form simple ’two-component‘ systems, and also sophisticated ’multi-component’ systems. The deltaproteobacterium Myxococcus xanthus contains a large repertoire of signaling proteins, many of which regulate its complex multicellular developmental program. In this respect, one important systems is the Esp signaling system, consisting of the hybrid histidine protein kinase, EspA, two serine/threonine protein kinases (PktA5 and PktB8), and a putative transport protein (EspB). In the presented study, I assign an orphan hybrid histidine protein kinase, EspC, to the Esp signaling system which negatively regulates progression through the M. xanthus developmental program. The genetic analysis revealed that EspC is an essential component of this system, because ΔespA, ΔespC, and ΔespAΔespC double mutants shared an identical early developmental phenotype. Surprisingly, disruption of EspC’s auto-phosphorylation in vivo did not produce a mutant developmental phenotype, whereas substitution of its phospho-accepting residue within the receiver domain resulted in the null phenotype. Furthermore, it is shown that although the EspC histidine kinase could efficiently autophosphorylate in vitro, it did not act as a phospho-donor to its own receiver domain. Instead, both, in vitro and in vivo analyses elucidated that the phospho-donor instead is EspA’s histidine kinase. Therefore, EspA and EspC participate in a novel hybrid histidine protein kinase signaling mechanism involving both inter- and intraprotein phosphotransfer. This inter- and intraprotein phosphotransfer results in the combined phosphorylation of EspA’s and EspC’s receiver domains which represents the output of the Esp signaling system. Further genetic analyses suggested that this Esp system is regulated on the level of its phosphatase activity, likely involving the sensing domains of EspC for regulation. Finally, I uncovered that the Esp system stimulates the proteolytic turnover of MrpC, a crucial transcription factor of the developmental program, via as yet unidentified serine protease. Altogether, these data unravel a novel signaling mechanism of His-Asp signaling systems, and thus expand the knowledge about the complexity and plasticity of these crucial signal transduction systems.

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