Bacteria were thought to be devoid of tyrosine-phosphorylating enzymes. However, several tyrosine kinases without similarity to their eukaryotic counterparts have recently been identified in bacteria. They are involved in many physiological processes, but their accurate functions remain poorly understood due to slow progress in their structural characterization. They have been best characterized as copolymerases involved in the synthesis and export of extracellular polysaccharides. These compounds play critical roles in the virulence of pathogenic bacteria, and bacterial tyrosine kinases can thus be considered as potential therapeutic targets. Here, we present the crystal structures of the phosphorylated and unphosphorylated states of the tyrosine kinase CapB from the human pathogen Staphylococcus aureus together with the activator domain of its cognate transmembrane modulator CapA. This first high-resolution structure of a bacterial tyrosine kinase reveals a 230-kDa ring-shaped octamer that dissociates upon intermolecular autophosphorylation. These observations provide a molecular basis for the regulation mechanism of the bacterial tyrosine kinases and give insights into their copolymerase function.

The ATM kinase and p53 are key tumor suppressor factors that control the genotoxic stress response pathway. The ATM substrate Mdm2 controls p53 activity by either targeting p53 for degradation or promoting its synthesis by binding the p53 mRNA. The physiological role and regulation of Mdm2's dual function toward p53 is not known. Here we show that ATM-dependent phosphorylation of Mdm2 at Ser395 is required for the p53 mRNA-Mdm2 interaction. This event also promotes SUMO-conjugation of Mdm2 and its nucleoli accumulation. Interfering with the p53 mRNA-Mdm2 interaction prevents p53 stabilization and activation following DNA damage. These results demonstrate how ATM activity switches Mdm2 from a negative to a positive regulator of p53 via the p53 mRNA.

MDM2 is considered a hub protein due to its capacity to interact with a large number of different partners of which p53 is most well described. MDM2 is an E3 ubiquitin ligase, and many, but not all, of its interactions relate directly to this activity, such as substrates, adaptors or bridges, promoters, inhibitors or complementary factors. Some interactions serve regulatory functions that in response to cellular stresses control the localisation and functions of MDM2 including protein kinases, ribosomal proteins and proteases. Moreover, interactions with nucleotides serve other functions such as mRNA to regulate protein synthesis and DNA to control transcription. To perform such a pleiotropic panorama of different functions, MDM2 is subjected to a multitude of post-translational modifications and is expressed in different isoforms. The large and diverse interactome is made possible due to the plasticity of MDM2 and in this review we have listed the MDM2 interactions until now and we will discuss how this multifaceted protein can interact with such a variety of substrates to provide a key intermediary role in different signalling pathways.