The HD domain, named after the conserved doublet of predicted catalytic residues, is found in a wide range of bacterial, archaeal and eukaryotic proteins. It defines a superfamily of phosphohydrolases that can catalyze both metal-dependent and -independent phosphomonoesterase and phosphodiesterase reactions for a broad range of substrates [1,2]:

• Bacterial dGTPase.
• Bacterial polyA polymerases.
• Bacterial CCA-adding enzymes, catalyze the addition and repair of the essential 3'-terminal CCA sequence in tRNAs without using a nucleic acid template.
• Bacterial uridylyl transferases (GlnD).
• Bacterial stringent-response guanosine polyphosphate [ppgpp(p)] hydrolase/ synthetase (SpoT/RelA).
• Fungal cyanamide lyase.

The HD-domain proteins appear to be involved in nucleic acid and nucleotide metabolism, signal transduction and possibly other functions. They are diverse in terms of both domain architecture and phylogenetic distribution; each of the completely sequenced genomes encodes more than one version of this domain.

The HD domain is composed of a bundle of α helices with a 5-helix core (see <PDB:2PAR>). Although all HD domains share key design features, a striking diversity of catalytic centres have been identified, containing no metal, mono-, bi- or trinuclear metal binding sites [2,3].

A distinct version of this domain, HD-GYP, contains a number of additional highly conserved residues. The spectrum of the domains that are associated with HD-GYP in multidomain proteins suggests that it is probably involved in signal transduction. The HD-GYP family of HD proteins so far is lacking in archaea and eukaryotes. The HD-GYP domain is likely to be a conserved scaffold whose main role is to allow protein-protein interactions with partner GGDEF domains (see <PDOC50887>) while achieving (a) different function(s) through diversification of the active-site cavity and the N-terminal regulatory domains [4,5,6].

• Xanthomonas campestris RpfG, a multi-phenotype protein involved in virulence, motility and biofilm regulation. It functions as cyclic di- 3',5'-GMP (c-di-GMP) degrading phosphodiesterase.
• Persephonella marina PmGH, a cyclic di-3',5'-GMP (c-di-GMP) phosphodiesterase.
• Bdellovibrio bacteriovorus Bd1817, a catalytically inactive protein.
• Pseudomonas aeruginosa PA4781 protein, a phosphodiesterase involved in cyclic di-3',5'-GMP (c-di-GMP) degradation.
• Pseudomonas aeruginosa PA4108 protein,
• Vibrio cholerae VCA0861, contains tandem HD and HD-GYP domains [6].

In addition to the HD domain 5-helix core, the HD-GYP domain contains two extra C-terminal helices (see <PDB:4MCW>) [3,5,7,8].

The HD-related output domain (HDOD) is a protein domain of unknown function. Proteins containing the HDOD are widespread in diverse bacteria; it can be present as a stand-alone domain, and also associated with other domains, such as response regulatory (RR) (see <PDOC50110>), GGDEF (see <PDOC50887>), and EAL (see <PDOC50883>), suggesting a role in regulation and signaling [9,10]:

• Campylobacter jejuni virulence factor CJ048, a stand-alone HDOD containing protein required for motility and involved in colonization of the chick gastrointestinal tract.
• Xanthomonas campestris pv. campestris (Xcc) GsmR (general stress and motility regulator), plays a role in the general stress response of Xcc and is involved in the expression of genes responsible for flagellum synthesis. It has a RR domain at the N-terminus and a C-terminal HDOD.
• Xanthomonas campestris pv. campestris (Xcc) HdpA, contains a HDOD at the N- terminus and a GGDEF domain at the C-terminus.
• Xanthomonas campestris pv. campestris (Xcc) HdpB, a stand-alone HDOD containing protein.

The HDOD domain folds into a complex arrangement of α helices (see <PDB:1VQR>) [11].

The profiles we developed cover respectively the core HD domain and the entire HD-GYP and HDOD domains.