A conserved scaffold with heterogeneous metal ion binding site: the multifaceted example of HD-GYP proteins

Cutruzzolà, Francesca; Paiardini, Alessandro; Rossi, Chiara Scribani; Spizzichino, Sharon; Paone, Alessio; Giardina, G.; Rinaldo, Serena

doi:10.1016/j.ccr.2021.214228

Cited by 4 publications

(4 citation statements)

References 51 publications

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“…The phosphodiesterase activity has also been observed with manganese (Mn 2+ ) ions (36,39). Some HD-GYP domains could bind Co 2+ , Ni 2+ , Mg 2+ , Zn 2+ , Ca 2+ , and Cu 2+ with similar affinities (Kd around 1 µM), and some of these metal complexes showed comparable catalytic activity (39,42,46,58), reviewed in (25).…”

Section: Substrate Binding and Hydrolysis By Hd-gyp Domainsmentioning

confidence: 98%

“…The catalytic mechanism of c-di-GMP hydrolysis by HD-GYP domains is believed to involve a nucleophilic attack on the phosphorus atom of the central ribose-phosphate ring by a hydroxide ion, activated by one or two Fe 2+ (or other Me 2+ ) ions of the active site (36). The mechanistic aspects of the phosphodiesterase activity of the HD-GYP domain and its allosteric regulation are described in detail in recent reviews (24,25).…”

Section: Substrate Binding and Hydrolysis By Hd-gyp Domainsmentioning

confidence: 99%

“…HD-GYP domains participate in bacterial regulatory cascades in two principal ways: by hydrolyzing cdi-GMP (and/or cGAMP) and by participating in complex protein-protein interactions (24,25). Like GGDEF and EAL, the other two domains involved in c-di-GMP metabolism, HD-GYPs are rarely seen in a stand-alone form.…”

Section: Regulatory Roles Of Hd-gyp-containing Proteinsmentioning

confidence: 99%

“…The second c-di-GMP-hydrolyzing domain, HD-GYP, has been the subject of far fewer studies and very few comprehensive reviews (22)(23)(24)(25). This domain, named after two of its conserved sequence motifs, was initially described in 1999 (3) as a specialized version of the widespread HD phosphohydrolase domain, which contains the metal-binding His-Asp active-site motif (26).…”

Section: Introductionmentioning

confidence: 99%

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Sequence conservation, domain architectures, and phylogenetic distribution of the HD-GYP type c-di-GMP phosphodiesterases

Galperin

Chou

2021

Preprint

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The HD-GYP domain, named after two of its conserved sequence motifs, was first described in 1999 as a specialized version of the widespread HD phosphohydrolase domain that had additional highly conserved amino acid residues. Domain associations of HD-GYP indicated its involvement in bacterial signal transduction and distribution patterns of this domain suggested that it could serve as a hydrolase of the bacterial second messenger c-di-GMP, in addition to or instead of the EAL domain. Subsequent studies confirmed the ability of various HD-GYP domains to hydrolyze c-di-GMP to linear pGpG and/or GMP. Certain HD-GYP-containing proteins hydrolyze another second messenger, cGAMP, and some HD-GYP domains participate in regulatory protein-protein interactions. The recently solved structures of HD-GYP domains from four distinct organisms clarified the mechanisms of c-di-GMP binding and metal-assisted hydrolysis. However, the HD-GYP domain is poorly represented in public domain databases, which causes certain confusion about its phylogenic distribution, functions, and domain architectures. Here, we present a refined sequence model for the HD-GYP domain and describe the roles of its most conserved residues in metal and/or substrate binding. We also calculate the numbers of HD-GYPs encoded in various genomes and list the most common domain combinations involving HD-GYP, such as the RpfG (REC–HD-GYP), Bd1817 (DUF3391– HD-GYP), and PmGH (GAF–HD-GYP) protein families. We also provide the descriptions of six HD-GYP–associated domains, including four novel integral membrane sensor domains. This work is expected to stimulate studies of diverse HD-GYP-containing proteins, their N-terminal sensor domains and the signals to which they respond.IMPORTANCEThe HD-GYP domain forms class II of c-di-GMP phosphodiesterases that control the cellular levels of the universal bacterial second messenger c-di-GMP and therefore affect flagellar and/or twitching motility, cell development, biofilm formation, and, often, virulence. Despite more than 20 years of research, HD-GYP domains are insufficiently characterized; they are often confused with ‘classical’ HD domains that are involved in various housekeeping activities and may participate in signaling, hydrolyzing (p)ppGpp and c-di-AMP. This work provides an updated description of the HD-GYP domain, including its sequence conservation, phylogenetic distribution, domain architectures, and the most widespread HD-GYP-containing protein families. This work shows that HD-GYP domains are widespread in many environmental bacteria and are predominant c-di-GMP hydrolases in many lineages, including clostridia and deltaproteobacteria.

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Section: Substrate Binding and Hydrolysis By Hd-gyp Domainsmentioning

confidence: 98%

Section: Substrate Binding and Hydrolysis By Hd-gyp Domainsmentioning

confidence: 99%

Section: Regulatory Roles Of Hd-gyp-containing Proteinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sequence conservation, domain architectures, and phylogenetic distribution of the HD-GYP type c-di-GMP phosphodiesterases

Galperin

Chou

2021

Preprint

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Insights into the molecular basis of c-di-GMP signalling in Pseudomonas aeruginosa

Feng

Zhou

Zhang

et al. 2022

Critical Reviews in Microbiology

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Sequence Conservation, Domain Architectures, and Phylogenetic Distribution of the HD-GYP Type c-di-GMP Phosphodiesterases

Galperin

Chou

2022

J Bacteriol

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The HD-GYP domain, named after two of its conserved sequence motifs, was first described in 1999 as a specialized version of the widespread HD phosphohydrolase domain that had additional highly conserved amino acid residues. Domain associations of HD-GYP indicated its involvement in bacterial signal transduction and distribution patterns of this domain suggested that it could serve as a hydrolase of the bacterial second messenger c-di-GMP, in addition to or instead of the EAL domain. Subsequent studies confirmed the ability of various HD-GYP domains to hydrolyze c-di-GMP to linear pGpG and/or GMP. Certain HD-GYP-containing proteins hydrolyze another second messenger, cGAMP, and some HD-GYP domains participate in regulatory protein-protein interactions. The recently solved structures of HD-GYP domains from four distinct organisms clarified the mechanisms of c-di-GMP binding and metal-assisted hydrolysis. However, the HD-GYP domain is poorly represented in public domain databases, which causes certain confusion about its phylogenetic distribution, functions, and domain architectures. Here, we present a refined sequence model for the HD-GYP domain and describe the roles of its most conserved residues in metal and/or substrate binding. We also calculate the numbers of HD-GYPs encoded in various genomes and list the most common domain combinations involving HD-GYP, such as the RpfG (REC–HD-GYP), Bd1817 (DUF3391– HD-GYP), and PmGH (GAF–HD-GYP) protein families. We also provide the descriptions of six HD-GYP–associated domains, including four novel integral membrane sensor domains. This work is expected to stimulate studies of diverse HD-GYP-containing proteins, their N-terminal sensor domains and the signals to which they respond. IMPORTANCE The HD-GYP domain forms class II of c-di-GMP phosphodiesterases that control the cellular levels of the universal bacterial second messenger c-di-GMP and therefore affect flagellar and/or twitching motility, cell development, biofilm formation, and, often, virulence. Despite more than 20 years of research, HD-GYP domains are insufficiently characterized; they are often confused with ‘classical’ HD domains that are involved in various housekeeping activities and may participate in signaling, hydrolyzing (p)ppGpp and c-di-AMP. This work provides an updated description of the HD-GYP domain, including its sequence conservation, phylogenetic distribution, domain architectures, and the most widespread HD-GYP-containing protein families. This work shows that HD-GYP domains are widespread in many environmental bacteria and are predominant c-di-GMP hydrolases in many lineages, including clostridia and deltaproteobacteria .

show abstract

A conserved scaffold with heterogeneous metal ion binding site: the multifaceted example of HD-GYP proteins

Cited by 4 publications

References 51 publications

Sequence conservation, domain architectures, and phylogenetic distribution of the HD-GYP type c-di-GMP phosphodiesterases

Sequence conservation, domain architectures, and phylogenetic distribution of the HD-GYP type c-di-GMP phosphodiesterases

Insights into the molecular basis of c-di-GMP signalling in Pseudomonas aeruginosa

Sequence Conservation, Domain Architectures, and Phylogenetic Distribution of the HD-GYP Type c-di-GMP Phosphodiesterases

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