A structural overview of the zinc transporters in the cation diffusion facilitator family

Cotrim, Camila A.; Jarrott, Russell; Martin, Jennifer L.; Drew, David

doi:10.1107/s2059798319003814

Cited by 46 publications

(45 citation statements)

References 80 publications

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“…These studies and those of other bacterial CDF proteins suggest the following common mechanism for CDF proteins: at a certain cytoplasmic metal cation concentration, cations bind to the CTD, locking it in a tighter packing when compared to its apo V-shape. This, in turn, facilitates the conformational change of the TMD thus enabling cations to be transported through this domain to the other side of the membrane Cherezov et al, 2008;Cotrim et al, 2019;Kolaj-Robin et al, 2015;Lopez-Redondo et al, 2018;Zeytuni et al, 2014b). Although previous MamM studies characterised some of the roles and the mechanism of the CTD in CDF proteins, one question remained unansweredwhether the CTD has a role in metal selectivity.…”

Section: Introductionmentioning

confidence: 99%

The cation diffusion facilitator protein MamM’s cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn²⁺

Barber-Zucker

Hall

Froes

et al. 2020

Preprint

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Cation diffusion facilitator (CDF) proteins are a conserved family of divalent transition metal cation transporters. CDF proteins are usually composed of two domains: the transmembrane domain (TMD), in which the metal cations are transported through, and a regulatory cytoplasmic C-terminal domain (CTD). Each CDF protein transports either one specific metal, or multiple metals, from the cytoplasm. Here, the model CDF protein MamM, from magnetotactic bacteria, was used to probe the role of the CTD in metal selectivity. Using a combination of biophysical and structural approaches, the binding of different metals to MamM CTD was characterized. Results reveal that different metals bind distinctively to MamM CTD in terms of; their binding sites, thermodynamics and binding-dependent conformation, both in crystal form and in solution. Furthermore, the results indicate that the CTD discriminates against Mn 2+ and provides the first direct evidence that CDF CTD's play a role in metal selectivity. KeywordsCation diffusion facilitator, magnetotactic bacteria, metal selectivity, protein-metal interactions, electron paramagnetic resonance (EPR) spectroscopy, pulsed electron double resonance (PELDOR) spectroscopy.

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Section: Introductionmentioning

confidence: 99%

The cation diffusion facilitator protein MamM’s cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn²⁺

Barber-Zucker

Hall

Froes

et al. 2020

Preprint

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“…Zinc exists as a variety of forms and acts as a cofactor in many proteins, such as transcriptional factors, metallothioneins, and various zinc-binding proteins [18,19]. A. fumigatus, which is a fungal pathogen, needs zinc to carry out physiological functions.…”

Section: Introductionmentioning

confidence: 99%

The Role of Zinc in Gliotoxin Biosynthesis of Aspergillus fumigatus

Seo

Kang

Park

et al. 2019

IJMS

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Zinc performs diverse physiological functions, and virtually all living organisms require zinc as an essential trace element. To identify the detailed function of zinc in fungal pathogenicity, we carried out cDNA microarray analysis using the model system of Aspergillus fumigatus, a fungal pathogen. From microarray analysis, we found that the genes involved in gliotoxin biosynthesis were upregulated when zinc was depleted, and the microarray data were confirmed by northern blot analysis. In particular, zinc deficiency upregulated the expression of GliZ, which encodes a Zn2-Cys6 binuclear transcription factor that regulates the expression of the genes required for gliotoxin biosynthesis. The production of gliotoxin was decreased in a manner inversely proportional to the zinc concentration, and the same result was investigated in the absence of ZafA, which is a zinc-dependent transcription activator. Interestingly, we found two conserved ZafA-binding motifs, 5′-CAAGGT-3′, in the upstream region of GliZ on the genome and discovered that deletion of the ZafA-binding motifs resulted in loss of ZafA-binding activity; gliotoxin production was decreased dramatically, as demonstrated with a GliZ deletion mutant. Furthermore, mutation of the ZafA-binding motifs resulted in an increase in the conidial killing activity of human macrophage and neutrophil cells, and virulence was decreased in a murine model. Finally, transcriptomic analysis revealed that the expression of ZafA and GliZ was upregulated during phagocytosis by macrophages. Taken together, these results suggest that zinc plays an important role in the pathogenicity of A. fumigatus by regulating gliotoxin production during the phagocytosis pathway to overcome the host defense system.

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“…In high DDMC concentrations, the DDMCs bind to specific metal binding sites in this domain, which causes a closure of the dynamic V-shaped apo form to a rigid and tighter conformation. This, in turn, facilitates the conformational change of the TMD from a cytoplasmic-facing conformation to an outermembrane / inner-compartmental-facing conformation which allows the release of the DDMCs 5, [12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

The metal binding site composition of the cation diffusion facilitator protein MamM cytoplasmic domain impacts its metal responsivity

Barber-Zucker

Shahar

Kolusheva

et al. 2020

Preprint

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The cation diffusion facilitator (CDF) is a conserved family of divalent d-block metal cation transporters that extrude these cations selectively from the cytoplasm. CDF proteins are composed of two domains: the transmembrane domain, through which the cations are transported, and a regulatory cytoplasmic Cterminal domain (CTD). Metal binding to the CTD leads to its tighter conformation, and this sequentially promotes conformational change of the transmembrane domain which allows the actual transport of specific metal cations. It was recently shown that the magnetotactic bacterial CDF protein MamM CTD has a role in metal selectivity, as binding of different metal cations exhibits distinctive affinities and conformations. It is yet unclear whether the composition of the CTD binding sites can impact metal selectivity. Here we performed a mutational study of MamM CTD, where we exchanged the metal binding residues with different metal-binding amino acids. Using X-ray crystallography and Trp-fluorescence spectrometry, we studied the impact of the mutations on the CTD conformation in the presence of different metals. Our results reveal that the incorporation of such mutations alters the domain response to metals in vitro, as mutant forms of the CTD bind metals differently in terms of the composition of the binding sites and the CTD conformation.

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A structural overview of the zinc transporters in the cation diffusion facilitator family

Cited by 46 publications

References 80 publications

The cation diffusion facilitator protein MamM’s cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn²⁺

The cation diffusion facilitator protein MamM’s cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn²⁺

The Role of Zinc in Gliotoxin Biosynthesis of Aspergillus fumigatus

The metal binding site composition of the cation diffusion facilitator protein MamM cytoplasmic domain impacts its metal responsivity

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A structural overview of the zinc transporters in the cation diffusion facilitator family

Cited by 46 publications

References 80 publications

The cation diffusion facilitator protein MamM’s cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn2+

The cation diffusion facilitator protein MamM’s cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn2+

The Role of Zinc in Gliotoxin Biosynthesis of Aspergillus fumigatus

The metal binding site composition of the cation diffusion facilitator protein MamM cytoplasmic domain impacts its metal responsivity

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Product

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The cation diffusion facilitator protein MamM’s cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn²⁺

The cation diffusion facilitator protein MamM’s cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn²⁺