Complex Structure and Biochemical Characterization of the Staphylococcus aureus cyclic di-AMP binding Protein PstA, the Founding Member of a New Signal Transduction Protein Family [Protein Structure and Folding]

December 12th, 2014 by Campeotto, I., Zhang, Y., Mladenov, M. G., Freemont, P. S., Grundling, A.

Signaling nucleotides are integral parts of signal transduction systems allowing bacteria to cope with and rapidly respond to changes in the environment. The Staphylococcus aureus PII-like signal transduction protein PstA was recently identified as a cyclic diadenylate monophosphate (c-di-AMP) binding protein. Here, we present the crystal structures of the apo and c-di-AMP bound PstA protein, which is trimeric in solution as well as in the crystals. The structures combined with a detailed bioinformatics analysis revealed that the protein belongs to a new family of proteins with a similar core fold but with distinct features to classical PII proteins, which usually function in nitrogen metabolism pathways in bacteria. The complex structure revealed three identical c-di-AMP binding sites per trimer with each binding site at a monomer-monomer interface. While distinctly different from other cyclic-di-nucleotide binding sites, as the half binding sites are not symmetrical, the complex structure also highlighted common features for c-di-AMP binding sites. A comparison between the apo and complex structures reveal a series of conformational changes that result in the ordering of two anti-parallel β-strands that protrude from each monomer and allowed us to propose a mechanism on how the PstA protein functions as a signaling transduction protein.
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