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Abstract
Bis-(3',5') cyclic di-guanylate (c-di-GMP) is a key bacterial second messenger that is implicated in the regulation of many crucial processes that include biofilm formation, motility and virulence. Cellular levels of c-di-GMP are controlled through synthesis by GGDEF domain diguanylate cyclases and degradation by two classes of phosphodiesterase with EAL or HD-GYP domains. Here, we have determined the structure of an enzymatically active HD-GYP domain protein from Persephonella marina (PmGH) alone, in complex with substrate (c-di-GMP) and final reaction product (GMP). The structures reveal a novel trinuclear iron binding site, which is implicated in catalysis and identify residues involved in recognition of c-di-GMP. This structure completes the picture of all domains involved in c-di-GMP metabolism and reveals that the HD-GYP family splits into two distinct subgroups containing bi- and trinuclear metal centres.
Highlights
Bis-(3′,5′) cyclic di-guanylate (c-di-GMP) is a second messenger utilized by almost all eubacteria that acts to regulate a wide range of functions including developmental transitions, adhesion, biofilm formation, motility and the synthesis of virulence factors (Schirmer and Jenal, 2009; Boyd and O’Toole, 2012)
Bis-(3′,5′) cyclic di-guanylate (c-di-GMP) is a key bacterial second messenger that is implicated in the regulation of many crucial processes that include biofilm formation, motility and virulence
Cellular levels of c-di-GMP are controlled through synthesis by GGDEF domain diguanylate cyclases and degradation by two classes of phosphodiesterase with EAL or HD-GYP domains
Summary
Bis-(3′,5′) cyclic di-guanylate (c-di-GMP) is a second messenger utilized by almost all eubacteria that acts to regulate a wide range of functions including developmental transitions, adhesion, biofilm formation, motility and the synthesis of virulence factors (Schirmer and Jenal, 2009; Boyd and O’Toole, 2012). C-di-GMP is synthesized from two GTP molecules by GGDEF domain-containing diguanylate cyclases (DGCs) and degraded by phosphodiesterases (PDEs) with either an EAL or HD-GYP domain (Ryan et al, 2006; Hengge, 2009; Schirmer and Jenal, 2009; Boyd and O’Toole, 2012). Three-dimensional structures have been determined for GGDEF and EAL domains, and have afforded detailed insight into their roles in the turnover of c-di-GMP and regulatory interactions with other proteins (Hengge, 2009; Schirmer and Jenal, 2009; Boyd and O’Toole, 2012). This work identified a binuclear iron centre and the role of conserved residues within the HD-GYP family (to include the HD diad) in metal binding. The determination of the structure of Bd1817 may afford some insight into metal binding by enzymatically active HD-GYP domains, but the protein lacks the conserved tyrosine of the GYP motif and has no c-di-GMP phosphodiesterase activity, precluding insights into the role of the other conserved residues
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