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Metalloproteins: How Metals Shape Protein Structure and Function

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (20 May 2024) | Viewed by 4155

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Guest Editor
Dipartimento di Scienze biochimiche ‘A. Rossi Fanelli’, Università degli Studi di Roma La Sapienza, Rome, Italy
Interests: iron; copper; multicopper oxidase; ceruloplasmin; ferroportin; lactoferrin; neurodegeneration; oxidative stress; yeast; membrane proteins
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Special Issue Information

Dear Colleagues,

Metal ions play a critical role as structural, catalytic and signaling components of proteins in all living organisms. Metalloproteins can bind single or multiple metals in the form of simple ions, clusters or with cofactors of varying complexity. Transition metals such as Fe, Cu, Mn and the post-transition metal Zn are involved in a remarkably wide variety of cellular processes, ranging from respiration to photosynthesis, nitrogen fixation, the Krebs cycle, oxygen transport, antioxidant defense, DNA synthesis and gene regulation, among others. Other transition metals such as Co, Mo, Ni, V and W are much less frequent in proteins; however, they are also essential for key biochemical reactions in all kingdoms of life. Metal coordination and chemistry shape protein structure and function, so it is not surprising that defects in metal homeostasis (either due to excess or deficiency) often lead to pathological states.

This Special Issue of IJMS welcomes contributions in all areas of metalloprotein biology and biophysics, including the relation between molecular structure, mechanism and function, metal-mediated regulation and signaling, roles in health and disease and techniques for the study of metalloproteins. Original papers and review articles on these and related topics are welcome.

Dr. Maria Carmela Bonaccorsi Di Patti
Guest Editor

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Keywords

  • transition metals
  • metal clusters
  • structure
  • catalysis
  • regulation
  • electron transfer
  • metalloenzymes
  • metal transporters
  • metal sensors
  • heavy metal toxicity

Published Papers (4 papers)

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Research

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16 pages, 2316 KiB  
Article
Exploring the Influence of Zinc Ions on the Conformational Stability and Activity of Protein Disulfide Isomerase
by Ana Iochabel Soares Moretti, Viktoria E. Baksheeva, Andrei Yu. Roman, Tiphany Coralie De Bessa, François Devred, Hervé Kovacic and Philipp O. Tsvetkov
Int. J. Mol. Sci. 2024, 25(4), 2095; https://doi.org/10.3390/ijms25042095 - 8 Feb 2024
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Abstract
The interplay between metal ion binding and the activity of thiol proteins, particularly within the protein disulfide isomerase family, remains an area of active investigation due to the critical role that these proteins play in many vital processes. This research investigates the interaction [...] Read more.
The interplay between metal ion binding and the activity of thiol proteins, particularly within the protein disulfide isomerase family, remains an area of active investigation due to the critical role that these proteins play in many vital processes. This research investigates the interaction between recombinant human PDIA1 and zinc ions, focusing on the subsequent implications for PDIA1’s conformational stability and enzymatic activity. Employing isothermal titration calorimetry and differential scanning calorimetry, we systematically compared the zinc binding capabilities of both oxidized and reduced forms of PDIA1 and assessed the structural consequences of this interaction. Our results demonstrate that PDIA1 can bind zinc both in reduced and oxidized states, but with significantly different stoichiometry and more pronounced conformational effects in the reduced form of PDIA1. Furthermore, zinc binding was observed to inhibit the catalytic activity of reduced-PDIA1, likely due to induced alterations in its conformation. These findings unveil a potential regulatory mechanism in PDIA1, wherein metal ion binding under reductive conditions modulates its activity. Our study highlights the potential role of zinc in regulating the catalytic function of PDIA1 through conformational modulation, suggesting a nuanced interplay between metal binding and protein stability in the broader context of cellular redox regulation. Full article
(This article belongs to the Special Issue Metalloproteins: How Metals Shape Protein Structure and Function)
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19 pages, 3450 KiB  
Article
Identification, Biochemical Characterization, and In Vivo Detection of a Zn-Metalloprotease with Collagenase Activity from Mannheimia haemolytica A2
by Gerardo Ramírez-Rico, Moises Martinez-Castillo, Lucero Ruiz-Mazón, Erika Patricia Meneses-Romero, José Arturo Flores Palacios, Efrén Díaz-Aparicio, Erasmo Negrete Abascal and Mireya de la Garza
Int. J. Mol. Sci. 2024, 25(2), 1289; https://doi.org/10.3390/ijms25021289 - 20 Jan 2024
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Abstract
Respiratory diseases in ruminants are a main cause of economic losses to farmers worldwide. Approximately 25% of ruminants experience at least one episode of respiratory disease during the first year of life. Mannheimia haemolytica is the main etiological bacterial agent in the ruminant [...] Read more.
Respiratory diseases in ruminants are a main cause of economic losses to farmers worldwide. Approximately 25% of ruminants experience at least one episode of respiratory disease during the first year of life. Mannheimia haemolytica is the main etiological bacterial agent in the ruminant respiratory disease complex. M. haemolytica can secrete several virulence factors, such as leukotoxin, lipopolysaccharide, and proteases, that can be targeted to treat infections. At present, little information has been reported on the secretion of M. haemolytica A2 proteases and their host protein targets. Here, we obtained evidence that M. haemolytica A2 proteases promote the degradation of hemoglobin, holo-lactoferrin, albumin, and fibrinogen. Additionally, we performed biochemical characterization for a specific 110 kDa Zn-dependent metalloprotease (110-Mh metalloprotease). This metalloprotease was purified through ion exchange chromatography and characterized using denaturing and chaotropic agents and through zymography assays. Furthermore, mass spectrometry identification and 3D modeling were performed. Then, antibodies against the 110 kDa-Mh metalloprotease were produced, which achieved great inhibition of proteolytic activity. Finally, the antibodies were used to perform immunohistochemical tests on postmortem lung samples from sheep with suggestive histology data of pneumonic mannheimiosis. Taken together, our results strongly suggest that the 110-Mh metalloprotease participates as a virulence mechanism that promotes damage to host tissues. Full article
(This article belongs to the Special Issue Metalloproteins: How Metals Shape Protein Structure and Function)
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9 pages, 2856 KiB  
Article
Genetic Incorporation of Dansylalanine in Human Ferroportin to Probe the Alternating Access Mechanism of Iron Transport
by Matteo Amadei, Antonella Niro, Maria Rosaria Fullone, Rossella Miele, Fabio Polticelli, Giovanni Musci and Maria Carmela Bonaccorsi di Patti
Int. J. Mol. Sci. 2023, 24(15), 11919; https://doi.org/10.3390/ijms241511919 - 25 Jul 2023
Viewed by 855
Abstract
Ferroportin (Fpn), a member of the major facilitator superfamily (MFS) of transporters, is the only known iron exporter found in mammals and plays a crucial role in regulating cellular and systemic iron levels. MFSs take on different conformational states during the transport cycle: [...] Read more.
Ferroportin (Fpn), a member of the major facilitator superfamily (MFS) of transporters, is the only known iron exporter found in mammals and plays a crucial role in regulating cellular and systemic iron levels. MFSs take on different conformational states during the transport cycle: inward open, occluded, and outward open. However, the precise molecular mechanism of iron translocation by Fpn remains unclear, with conflicting data proposing different models. In this work, amber codon suppression was employed to introduce dansylalanine (DA), an environment-sensitive fluorescent amino acid, into specific positions of human Fpn (V46, Y54, V161, Y331) predicted to undergo major conformational changes during metal translocation. The results obtained indicate that different mutants exhibit distinct fluorescence spectra depending on the position of the fluorophore within the Fpn structure, suggesting that different local environments can be probed. Cobalt titration experiments revealed fluorescence quenching and blue-shifts of λmax in Y54DA, V161DA, and Y331DA, while V46DA exhibited increased fluorescence and blue-shift of λmax. These observations suggest metal-induced conformational transitions, interpreted in terms of shifts from an outward-open to an occluded conformation. Our study highlights the potential of genetically incorporating DA into Fpn, enabling the investigation of conformational changes using fluorescence spectroscopy. This approach holds great promise for the study of the alternating access mechanism of Fpn and advancing our understanding of the molecular basis of iron transport. Full article
(This article belongs to the Special Issue Metalloproteins: How Metals Shape Protein Structure and Function)
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Review

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20 pages, 700 KiB  
Review
For the Better or for the Worse? The Effect of Manganese on the Activity of Eukaryotic DNA Polymerases
by Eva Balint and Ildiko Unk
Int. J. Mol. Sci. 2024, 25(1), 363; https://doi.org/10.3390/ijms25010363 - 27 Dec 2023
Viewed by 855
Abstract
DNA polymerases constitute a versatile group of enzymes that not only perform the essential task of genome duplication but also participate in various genome maintenance pathways, such as base and nucleotide excision repair, non-homologous end-joining, homologous recombination, and translesion synthesis. Polymerases catalyze DNA [...] Read more.
DNA polymerases constitute a versatile group of enzymes that not only perform the essential task of genome duplication but also participate in various genome maintenance pathways, such as base and nucleotide excision repair, non-homologous end-joining, homologous recombination, and translesion synthesis. Polymerases catalyze DNA synthesis via the stepwise addition of deoxynucleoside monophosphates to the 3′ primer end in a partially double-stranded DNA. They require divalent metal cations coordinated by active site residues of the polymerase. Mg2+ is considered the likely physiological activator because of its high cellular concentration and ability to activate DNA polymerases universally. Mn2+ can also activate the known DNA polymerases, but in most cases, it causes a significant decrease in fidelity and/or processivity. Hence, Mn2+ has been considered mutagenic and irrelevant during normal cellular function. Intriguingly, a growing body of evidence indicates that Mn2+ can positively influence some DNA polymerases by conferring translesion synthesis activity or altering the substrate specificity. Here, we review the relevant literature focusing on the impact of Mn2+ on the biochemical activity of a selected set of polymerases, namely, Polβ, Polλ, and Polµ, of the X family, as well as Polι and Polη of the Y family of polymerases, where congruous data implicate the physiological relevance of Mn2+ in the cellular function of these enzymes. Full article
(This article belongs to the Special Issue Metalloproteins: How Metals Shape Protein Structure and Function)
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