Structure and Signaling Mechanism of a Zinc-Sensory Diguanylate Cyclase

Diguanylate cyclases synthesize the second messenger c-di-GMP, which in turn governs a plethora of physiological processes in bacteria. Although most diguanylate cyclases harbor sensory domains, their input signals are largely unknown. Here, we demonstrate that diguanylate cyclase DgcZ (YdeH) from Escherichia coli is regulated allosterically by zinc. Crystal structures show that the zinc ion is bound to the 3His/1Cys motif of the regulatory chemoreceptor zinc-binding domain, which mediates subunit contact within the dimeric enzyme. In vitro, zinc reversibly inhibits DgcZ with a subfemtomolar Ki constant. In vivo, bacterial biofilm formation is modulated by externally applied zinc in a DgcZ- and c-di-GMP-dependent fashion. The study outlines the structural principles of this zinc sensor. Zinc binding seems to regulate the activity of the catalytic GGDEF domains by impeding their mobility and thus preventing productive encounter of the two GTP substrates. •Diguanylate cyclase activity of DgcZ is allosterically regulated by zinc•Zinc binds tightly to the 1Cys/3His motif of the accessory CZB domain•In vivo, biofilm formation is regulated by zinc in a DgcZ-dependent manner•DgcZ activity is most likely inhibited by immobilization of the catalytic domains A large number of bacterial physiological processes is regulated by a second messenger cyclic dinucleotide c-di-GMP. Zähringer et al. show that a major E. coli phosphodiesterase that cleaves the cyclic dinucleotide c-di-GMP is allosterically regulated by zinc, which binds tightly to its regulatory domain.