InterPro: IPR014408 Signal transduction c-di-GMP phosphodiesterase, EAL/HD-GYP domain-containing

Members of this group contain signal transduction/regulatory domains EAL and modified HD-GYP. It should be noted that YuxH (ComB) protein from Bacillus subtilis, which was originally described as a transcriptional regulator of late competence genes, was later shown not to be required for this regulation [1].

Proteins containing these domains are an integral part or immediately downstream of the signalling cascade of two-component systems. The involvement of EAL domain in signal transduction was originally established in a study of BvgR protein, which acts as a repressor of vrg genes in Bordetella pertussis and is in turn controlled by the BvgAS two-component regulatory system [2]. EAL domain was found, in tandem with GGDEF domain, in diguanylate cyclases/phosphodiesterases involved in regulation of extracellular cellulose biosynthesis by cyclic diguanylate(c-di-GMP) [3, 4], a novel global second messenger in bacteria [5], see IPR012226 for details. Since the diguanylate cyclase activity has been assigned to the GGDEF domain by domain disruption experiments, the EAL domain has been predicted to act as diguanylate phosphodiesterase, which has been confirmed experimentally with Salmonella typhimurium AdrA [4].

HD-GYP is a conserved domain found in response regulator modules of various signal transduction systems. The involvement of the HD-GYP domain in signal transduction was originally proposed on the basis of its association with CheY-like and other signal transduction domains [6] and was later directly demonstrated experimentally by showing that RpfG is involved in regulation of the biosynthesis of extracellular endoglucanase and polysaccharide [7].

A modification of the HD-GYP domain, which is found in this group and in PIRSF026248, as well as in several smaller groups, lacks the conserved distal portion of the domain and has certain substitutions in the characteristic metal-binding residues [8] of the HD superfamily phosphohydrolases, which is likely to render it catalytically inactive. Note that HD domain IPR006674 is not recognised in many members of this group because it is a divergent form.

The exact mode of action and targets of the HD-GYP domain are not known [5]. The HD-GYP domain belongs to the domain group of metal-dependent phosphohydrolases designated the HD domain superfamily after the principal conserved residues implicated in metal binding and catalysis [8]. The version of the HD-type domain present in members of IPR008328, and in some other groups, has many additional highly conserved residues, including a conserved GYP motif, and is therefore called HD-GYP [6, 5]. It has been noted that the highly conserved sequence of the HD-GYP domain suggests high substrate specificity [5]. On the basis of its association with the GGDEF diguanylate cyclase domain, it has been also predicted that the HD-GYP domain may be involved in the metabolism of cyclic diguanylate or in dephosphorylation of some phosphotransfer domain [5].