Structures of the activator of
            <i>K. pneumonia</i>
            biofilm formation, MrkH, indicates PilZ domains involved in c-di-GMP and DNA binding

Schumacher, Maria A.; Zhang, Wenjie

doi:10.1073/pnas.1607503113

Cited by 43 publications

(39 citation statements)

References 36 publications

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“…In the past 12 years, more than 30 structures of various PilZ domains have been solved and deposited in the Protein DataBank (PDB), see Table S1. These include high-resolution crystal structures of the stand-alone PilZ domains, as well as PilZ domains from the bacterial cellulose synthase (BcsA and AcsAB), alginate production protein Alg44, flagellar brake proteins YcgR, VCA0042, and MotI, and the transcriptional regulator MrkH (22, 25-27, 34, 35, 38, 39, 41-43). As noted in the respective reports, most of these domains are very similar in sequence and structure.…”

Section: Resultsmentioning

confidence: 99%

“…The structure of MrkH, a transcriptional regulator of type 3 fimbriae production in Klebsiella pneumoniae (50), reveals yet another N-terminal six-stranded β-barrel domain (hereafter, PilZN2 domain) fused to a canonical PilZ domain (27, 38). In PilZN2, the C-terminal α-helix is lost, and the N-terminal loop is replaced by a short β-strand, followed by a 13-aa α-helix (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, in P. aeruginosa MapZ, this helix mediates the interaction of PilZ with the methyltransferase CheR (59). In K. pneumoniae MrkH, it has been implicated in binding DNA (38). In the cellulose synthase structure, the C-terminal α-helix of PilZ is split into two, which both pack against the glycosyltransferase domain (BcsA has an additional long C-terminal α-helix after the PilZ domain) (25, 60).…”

Section: Discussionmentioning

confidence: 99%

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Structural conservation and diversity of PilZ-related domains

Galperin

Chou

2019

Preprint

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The widespread bacterial second messenger cyclic diguanylate (c-di-GMP) regulates a 1 variety of processes, including protein secretion, motility, cell development, and biofilm 2 formation. C-di-GMP-dependent responses are often mediated by its binding to the 3 cytoplasmic receptors that contain the PilZ domain. We present here comparative 4 structural and sequence analysis of various PilZ-related domains and describe three 5 principal types of them: (i) the canonical PilZ domain, whose structure includes a six-6 stranded beta-barrel and a C-terminal alpha-helix; (ii) an atypical PilZ domain that 7 contains two extra alpha-helices and forms stable tetramers, and (iii) divergent PilZ-8 related domains, which include the eponymous PilZ protein and PilZN (YcgR_N) and 9 PilZNR (YcgR_2) domains. We refine the second c-di-GMP binding motif of PilZ as 10 [D/N]hSxxG and show that the hydrophobic residue h of this motif interacts with a cluster 11 of conserved hydrophobic residues, helping maintain the PilZ domain fold. We describe 12 several novel PilZN-type domains that are fused to the canonical PilZ domains in specific 13 taxa, such as spirochetes, actinobacteria, cellulosolytic clostridia, deltaproteobacteria, 14 and aquificae. We propose that the evolution of three major groups of PilZ domains 15 included (i) fusion of pilZ with other genes, which produced Alg44, cellulose synthase, and 16 other multidomain proteins; (ii) insertion of a ~200-bp fragment, which resulted in the 17 formation of tetramer-forming PilZ proteins, and (iii) tandem duplication of pilZ genes, 18 which led to the formation of PilZ dimers and YcgR-like proteins. 19 IMPORTANCE 20Cyclic di-GMP is a ubiquitous bacterial second messenger that regulates motility, biofilm 21 formation and virulence of many bacterial pathogens. The PilZ domain is a widespread c-22 di-GMP receptor that binds c-di-GMP through its RxxxR and [D/N]xSxxG motifs; some PilZ 23 domains lack these motifs and are unable to bind c-di-GMP. We used structural and 24 sequence analysis to assess the diversity of PilZ-related domains and define their common 25 features. We show that the hydrophobic residue h in the second motif is highly conserved; 26 it may serve as a readout for c-di-GMP binding. We describe three principal classes of 27 PilZ-related domains: canonical, tetramer-forming, and divergent PilZ domains, and 28 propose the evolutionary pathways that led to the emergence of these PilZ types. 29 30

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Structural conservation and diversity of PilZ-related domains

Galperin

Chou

2019

Preprint

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“…For hypothesis generation, an SSN is most valuable when nodes are segregated into isofunctional clusters. The reference nodes or functionally characterized PilZ proteins were instrumental in guiding the segregation 21 of nodes into putative isofunctional clusters. The formation of isofunctional clusters is also bolstered by the observation that functionally important residues are generally conserved in the putative isofunctional clusters or subclusters.…”

Section: Discussionmentioning

confidence: 99%

“…The core of PilZ domain features a β-barrel of 68-74 residues [5][6][21][22] . The canonical c-di-GMP-binding PilZ domain is also characterized by a flexible N-terminal loop (12-18 amino acids) that harbors the key RxxxR motif involved in direct c-di-GMP binding.…”

Section: Classification Of Pilz Proteins Into Single Di-and Multi-domentioning

confidence: 99%

Large-scale sequence similarity analysis reveals the scope of sequence and function divergence in PilZ domain proteins

Cheang

Sheng

et al. 2020

Preprint

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PilZ domain-containing proteins constitute a superfamily of widely distributed bacterial signalling proteins. Although studies have established the canonical PilZ domain as an adaptor protein domain evolved to specifically bind the second messenger c-di-GMP, mounting evidence suggest that the PilZ domain has undergone enormous divergent evolution to generate a superfamily of proteins that are characterized by a wide range of c-di-GMP-binding affinity, binding partners and cellular functions. The divergent evolution has even generated families of non-canonical PilZ domains that completely lack c-di-GMP binding ability. In this study, we performed a large-scale sequence analysis on more than 28,000 single-and di-domain PilZ proteins using the sequence similarity networking tool created originally to analyse functionally diverse enzyme superfamilies. The sequence similarity networks (SSN) generated by the analysis feature a large number of putative isofunctional protein clusters, and thus, provide an unprecedented panoramic view of the sequence-function relationship and function diversification in PilZ proteins. Some of the protein clusters in the networks are considered as unexplored clusters that contain proteins with completely unknown biological function;whereas others contain one, two or a few functionally known proteins, and therefore, enabling us to infer the cellular function of uncharacterized homologs or orthologs. With the ultimate goal of elucidating the diverse roles played by PilZ proteins in bacterial signal transduction, the work described here will facilitate the annotation of the vast number of PilZ proteins encoded by bacterial genome and help to prioritize functionally unknown PilZ proteins for future studies.3 Importance Although PilZ domain is best known as the protein domain evolved specifically for the binding of the second messenger c-di-GMP, divergent evolution has generated a superfamily of PilZ proteins with a diversity of ligand or protein-binding properties and cellular functions.We analysed the sequences of more than 28,000 PilZ proteins using the sequence similarity networking (SSN) tool to yield a global view of the sequence-function relationship and function diversification in PilZ proteins. The results will facilitate the annotation of the vast number of PilZ proteins encoded by bacterial genomes and help us prioritize PilZ proteins for future studies.

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The global regulation of c‐di‐GMP and cAMP in bacteria

Liu,

Shi,

Jensen

et al. 2024

mLife

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Nucleotide second messengers are highly versatile signaling molecules that regulate a variety of key biological processes in bacteria. The best‐studied examples are cyclic AMP (cAMP) and bis‐(3′–5′)‐cyclic dimeric guanosine monophosphate (c‐di‐GMP), which both act as global regulators. Global regulatory frameworks of c‐di‐GMP and cAMP in bacteria show several parallels but also significant variances. In this review, we illustrate the global regulatory models of the two nucleotide second messengers, compare the different regulatory frameworks between c‐di‐GMP and cAMP, and discuss the mechanisms and physiological significance of cross‐regulation between c‐di‐GMP and cAMP. c‐di‐GMP responds to numerous signals dependent on a great number of metabolic enzymes, and it regulates various signal transduction pathways through its huge number of effectors with varying activities. In contrast, due to the limited quantity, the cAMP metabolic enzymes and its major effector are regulated at different levels by diverse signals. cAMP performs its global regulatory function primarily by controlling the transcription of a large number of genes via cAMP receptor protein (CRP) in most bacteria. This review can help us understand how bacteria use the two typical nucleotide second messengers to effectively coordinate and integrate various physiological processes, providing theoretical guidelines for future research.

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Structures of the activator of K. pneumonia biofilm formation, MrkH, indicates PilZ domains involved in c-di-GMP and DNA binding

Cited by 43 publications

References 36 publications

Structural conservation and diversity of PilZ-related domains

Structural conservation and diversity of PilZ-related domains

Large-scale sequence similarity analysis reveals the scope of sequence and function divergence in PilZ domain proteins

The global regulation of c‐di‐GMP and cAMP in bacteria

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