The Wor1-like Protein Fgp1 Regulates Pathogenicity, Toxin Synthesis and Reproduction in the Phytopathogenic Fungus Fusarium graminearum

Jonkers, Wilfried; Dong, Yanhong; Broz, Karen; Kistler, H. Corby

doi:10.1371/journal.ppat.1002724

Cited by 112 publications

(134 citation statements)

References 63 publications

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“…The white-opaque switching model has wide-ranging significance. Although the impact of white-opaque switching on C. albicans virulence is unclear (42,43), Wor1 orthologs in other fungal pathogens of mammals (44) and plants (45)(46)(47) are clearly determinants of virulence. Meta-analysis has shown that the architecture and stability of the white-opaque transcriptional circuit share many properties with those of the Oct4 circuit, which governs the pluripotency and differentiation of mouse embryonic stem cells (36).…”

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confidence: 99%

Differential Regulation of White-Opaque Switching by Individual Subunits of Candida albicans Mediator

2013

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The multisubunit eukaryotic Mediator complex integrates diverse positive and negative gene regulatory signals and transmits them to the core transcription machinery. Mutations in individual subunits within the complex can lead to decreased or increased transcription of certain subsets of genes, which are highly specific to the mutated subunit. Recent studies suggest a role for Mediator in epigenetic silencing. Using white-opaque morphological switching in Candida albicans as a model, we have shown that Mediator is required for the stability of both the epigenetic silenced (white) and active (opaque) states of the bistable transcription circuit driven by the master regulator Wor1. Individual deletions of eight C. albicans Mediator subunits have shown that different Mediator subunits have dramatically diverse effects on the directionality, frequency, and environmental induction of epigenetic switching. Among the Mediator deletion mutants analyzed, only Med12 has a steady-state transcriptional effect on the components of the Wor1 circuit that clearly corresponds to its effect on switching. The MED16 and MED9 genes have been found to be among a small subset of genes that are required for the stability of both the white and opaque states. Deletion of the Med3 subunit completely destabilizes the opaque state, even though the Wor1 transcription circuit is intact and can be driven by ectopic expression of Wor1. The highly impaired ability of the med3 deletion mutant to mate, even when Wor1 expression is ectopically induced, reveals that the activation of the Wor1 circuit can be decoupled from the opaque state and one of its primary biological consequences.

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Differential Regulation of White-Opaque Switching by Individual Subunits of Candida albicans Mediator

2013

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“…Gti1 plays a role in regulation of gluconate uptake in Schizosaccharomyces pombe [19]. The Wor1 homologs from several necrotrophic plant pathogens are all important for pathogenesis and toxin synthesis [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of the WOPR-DNA complex and implications for Wor1 function in white-opaque switching of Candida albicans

Zhang

Yan

et al. 2014

Cell Res

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Wor1 (white-opaque switching regulator 1) is a master regulator of the white-opaque switching in Candida albicans, an opportunistic human fungal pathogen, and is associated with its pathogenicity and commensality. Wor1 contains a conserved DNA-binding region at the N-terminus, consisting of two conserved segments (WOPRa and WOPRb) connected by a non-conserved linker that can bind to specific DNA sequences of the promoter regions and then regulates the transcription. Here, we report the crystal structure of the C. albicans Wor1 WOPR segments in complex with a double-stranded DNA corresponding to one promoter region of WOR1. The sequentially separated WOPRa and WOPRb are structurally interwound together to form a compact globular domain that we term the WOPR domain. The WOPR domain represents a new conserved fungal-specific DNA-binding domain which uses primarily a conserved loop to recognize and interact specifically with a conserved 6-bp motif of the DNA in both minor and major grooves. The protein-DNA interactions are essential for WOR1 transcriptional regulation and whiteto-opaque switching. The structural and biological data together reveal the molecular basis for the recognition and binding specificity of the WOPR domain with its specific DNA sequences and the function of Wor1 in the activation of transcription.

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“…1A), including the human pathogens Candida albicans (1-3), Histoplasma capsulatum (4), and Cryptococcus neoformans (5) and several plant pathogens (6)(7)(8)(9). In C. albicans, Wor1 controls the process of white-opaque switching and mating (1)(2)(3), and it has a key role in promoting commensalism (10).…”

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Structure of a new DNA-binding domain which regulates pathogenesis in a wide variety of fungi

Lohse¹,

Rosenberg

Cox³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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WOPR-domain proteins are found throughout the fungal kingdom where they function as master regulators of cell morphology and pathogenesis. Genetic and biochemical experiments previously demonstrated that these proteins bind to specific DNA sequences and thereby regulate transcription. However, their primary sequence showed no relationship to any known DNA-binding domain, and the basis for their ability to recognize DNA sequences remained unknown. Here, we describe the 2.6-Å crystal structure of a WOPR domain in complex with its preferred DNA sequence. The structure reveals that two highly conserved regions, separated by an unconserved linker, form an interdigitated β-sheet that is tilted into the major groove of DNA. Although the main interaction surface is in the major groove, the highest-affinity interactions occur in the minor groove, primarily through a deeply penetrating arginine residue. The structure reveals a new, unanticipated mechanism by which proteins can recognize specific sequences of DNA.fungal pathogenesis | transcription factor | transcriptional regulation | protein-DNA interaction | Candida albicans T he WOPR family of transcriptional regulators [named for the members Wor1 (white-opaque regulator 1), Pac2 (pat1 compensator 2), and Ryp1 (required for yeast phase growth 1)] controls morphological changes and pathogenesis in a diverse group of fungal species (Fig. 1A), including the human pathogens Candida albicans (1-3), Histoplasma capsulatum (4), and Cryptococcus neoformans (5) and several plant pathogens (6-9). In C. albicans, Wor1 controls the process of white-opaque switching and mating (1-3), and it has a key role in promoting commensalism (10). In H. capsulatum, it controls the transition from the mycelia form (found in soil) and the yeast form (found in infected human hosts) (4). Recently, a series of in vitro and in vivo experiments demonstrated that the WOPR domain of Wor1 binds DNA in a sequence-specific fashion and defined the DNA sequence recognized by it (Fig. 1B) (11,12). Muc1 expressed independent of TEC1 1 (Mit1) from Saccharomyces cerevisiae, a fourth WOPR-domain protein, and Ryp1 from H. capsulatum have since been shown to recognize this same DNA sequence, representing conservation of the WOPR domain-DNA sequence interactions over a period of 600 million to 1.2 billion years (13).Biochemical experiments indicated that the WOPR domain binds DNA in an unusual way. The WOPR domain consists of two regions conserved across many fungal species (referred to here as "R1" and "R2"), separated by a poorly conserved "linker" region of variable length (Fig. 1C). R1 is 80 aa in length, R2 is 50 aa, and the linker ranges from less than 25 to more than 100 aa, depending on the species. The WOPR domain alone can bind DNA tightly (∼5 nM) and specifically (11). Additional experiments demonstrated that neither R1 nor R2 alone could bind to DNA individually, but binding was observed-albeit at lower affinity-when the two regions were expressed as separate peptides and mixed in the presence of DNA. ...

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The Wor1-like Protein Fgp1 Regulates Pathogenicity, Toxin Synthesis and Reproduction in the Phytopathogenic Fungus Fusarium graminearum

Cited by 112 publications

References 63 publications

Differential Regulation of White-Opaque Switching by Individual Subunits of Candida albicans Mediator

Differential Regulation of White-Opaque Switching by Individual Subunits of Candida albicans Mediator

Crystal structure of the WOPR-DNA complex and implications for Wor1 function in white-opaque switching of Candida albicans

Structure of a new DNA-binding domain which regulates pathogenesis in a wide variety of fungi

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