Catalysis and regulation of cyclic dinucleotide specific phosphodiesterases

Abstract

In recent years, cyclic-di-GMP (c-di-GMP) has been firmly established as a major bacterial second messenger; whereas the structurally similar c-di-AMP has also emerged as another previously hidden messenger in prokaryotes. How the degradation of c-di-GMP and c-di-AMP is catalyzed and regulated remains poorly understood. We elucidated the catalytic mechanism of RocR, an EAL-domain containing c-di-GMP specific phosphodiesterase (PDE) from the opportunistic pathogen P. aeruginosa. We identified a conserved functional loop that is critical for the enzymatic activity and likely to be involved in the regulation of EAL domain. In addition, we discovered that the DHH domain-containing protein YybT is an efficient c-di-AMP-specific PDE. The PAS domain of YybT was unexpectedly found to bind them and regulate the PDE activity in response to them or nitric oxide. These biochemical and biophysical results not only yielded insight into the catalytic and regulatory mechanisms of the cyclic dinucleotide degrading proteins, but also unearthed a large number of catalytic inactive EAL domain protein from the bacterial genomes.