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Design and Application of Metal-Binding Proteins

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 31301

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Special Issue Editor

Prof. Dr. Aimin Liu

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Guest Editor

Department of Chemistry, The University of Texas at San Antonio, San Antonio, TX, USA
Interests: metalloproteins; protein engineering; protein evolution; transition metals; metals in biology

Special Issue Information

Dear Colleagues,

Metal-binding proteins are ubiquitously employed across all kingdoms of life to perform a remarkable array of critical functions. In metabolic pathways, the committed, irreversible, or key regulatory reaction steps are often mediated by metalloenzymes. Other than catalysis, Metal-binding proteins perform heavy metal accumulation, cellular sensing and signaling, gene regulation, transfer (e.g., electron, O2), and structural roles linked to protein-protein or protein-DNA interactions. Reaching a satisfying understanding of the mechanisms by which metals carry out these functions requires the coordinated application of many approaches and expertise from many disciplines. The knowledge gained has already been widely utilized to design metal-binding proteins and peptides for bioremediation, detoxification, biomedical imaging, biofuel, and synthesis of pharmaceuticals. One of the latest Nobel prizes in Chemistry was awarded last year to Dr. Frances H. Arnold “for the directed evolution of enzymes,” highlighting the pioneering work and accomplishments in the protein engineering field for creating new enzymes to manufacture everything that brings the most significant benefit to humankind. This major award was also a call to the scientific community for more attention and appreciation for protein design and applications. In this Special Issue, we invite investigators to contribute original research articles, as well as review articles that are related to the design and implementation of metal-binding proteins. We are particularly interested in but are not limited to, research that involves de novo protein design, directed evolution, rational design of metal-binding proteins, including using genetic code expansion approaches, for both mechanistic understandings and industrial or medical applications.

Prof. Aimin Liu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Metals in biology
Protein engineering
Protein design
Directed evolution
Metalloproteins
Metals in medicine
Metals in signaling
Protein structure-function relationships
Unnatural amino acid

Published Papers (6 papers)

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Research

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14 pages, 1854 KiB

Open AccessArticle

Mutations in Superoxide Dismutase 1 (Sod1) Linked to Familial Amyotrophic Lateral Sclerosis Can Disrupt High-Affinity Zinc-Binding Promoted by the Copper Chaperone for Sod1 (Ccs)

by Stefanie D. Boyd, Morgan S. Ullrich, Jenifer S. Calvo, Fatemeh Behnia, Gabriele Meloni and Duane D. Winkler

Molecules 2020, 25(5), 1086; https://doi.org/10.3390/molecules25051086 - 28 Feb 2020

Cited by 20 | Viewed by 5243

Abstract

Zinc (II) ions (hereafter simplified as zinc) are important for the structural and functional activity of many proteins. For Cu, Zn superoxide dismutase (Sod1), zinc stabilizes the native structure of each Sod1 monomer, promotes homo-dimerization and plays an important role in activity by “softening” the active site so that copper cycling between Cu(I) and Cu(II) can rapidly occur. Previously, we have reported that binding of Sod1 by its copper chaperone (Ccs) stabilizes a conformation of Sod1 that promotes site-specific high-affinity zinc binding. While there are a multitude of Sod1 mutations linked to the familial form of amyotrophic lateral sclerosis (fALS), characterizations by multiple research groups have been unable to realize strong commonalities among mutants. Here, we examine a set of fALS-linked Sod1 mutations that have been well-characterized and are known to possess variation in their biophysical characteristics. The zinc affinities of these mutants are evaluated here for the first time and then compared with the previously established value for wild-type Sod1 zinc affinity. Ccs does not have the same ability to promote zinc binding to these mutants as it does for the wild-type version of Sod1. Our data provides a deeper look into how (non)productive Sod1 maturation by Ccs may link a diverse set of fALS-Sod1 mutations. Full article

(This article belongs to the Special Issue Design and Application of Metal-Binding Proteins)

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17 pages, 2285 KiB

Open AccessArticle

The Tomato Metallocarboxypeptidase Inhibitor I, which Interacts with a Heavy Metal-Associated Isoprenylated Protein, Is Implicated in Plant Response to Cadmium

by Anna Manara, Elisa Fasani, Barbara Molesini, Giovanni DalCorso, Federica Pennisi, Tiziana Pandolfini and Antonella Furini

Molecules 2020, 25(3), 700; https://doi.org/10.3390/molecules25030700 - 6 Feb 2020

Cited by 24 | Viewed by 3510

Abstract

Metallocarboxypeptidases are metal-dependent enzymes, whose biological activity is regulated by inhibitors directed on the metal-containing active site. Some metallocarboxypeptidase inhibitors are induced under stress conditions and have a role in defense against pests. This paper is aimed at investigating the response of the tomato metallocarboxypeptidase inhibitor (TCMP)-1 to Cd and other abiotic stresses. To this aim, the tomato TCMP-1 was ectopically expressed in the model species Arabidopsis thaliana, and a yeast two-hybrid analysis was performed to identify interacting proteins. We demonstrate that TCMP-1 is responsive to Cd, NaCl, and abscisic acid (ABA) and interacts with the tomato heavy metal-associated isoprenylated plant protein (HIPP)26. A. thaliana plants overexpressing TCMP-1 accumulate lower amount of Cd in shoots, display an increased expression of AtHIPP26 in comparison with wild-type plants, and are characterized by a modulation in the expression of antioxidant enzymes. Overall, these results suggest a possible role for the TCMP-1/HIPP26 complex in Cd response and compartmentalization. Full article

(This article belongs to the Special Issue Design and Application of Metal-Binding Proteins)

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11 pages, 1839 KiB

Open AccessArticle

The Biochemical and Functional Characterization of M28 Aminopeptidase Protein Secreted by Acanthamoeba spp. on Host Cell Interaction

by Jian-Ming Huang, Yao-Tsung Chang and Wei-Chen Lin

Molecules 2019, 24(24), 4573; https://doi.org/10.3390/molecules24244573 - 13 Dec 2019

Cited by 5 | Viewed by 2795

Abstract

Acanthamoeba are a free-living protozoan whose pathogenic strain can cause severe human diseases, such as granulomatous encephalitis and keratitis. As such, the pathogenic mechanism between humans and Acanthamoeba is still unknown. In our previous study, we identified the secreted Acanthamoeba M28 aminopeptidase (M28AP) and then suggested that M28AP can degrade human C3b and iC3b for inhibiting the destruction of Acanthamoeba spp. with the human immune response. We constructed the produced the recombinant M28AP from a CHO cell, which is a mammalian expression system, to characterize the biochemical properties of Acanthamoeba M28AP. The recombinant M28AP more rapidly hydrolyzed Leu-AMC than Arg-AMC and could be inhibited by EDTA treatment. We show that recombinant M28AP can be delivered into the individual cell line and cause cell line apoptosis in a co-culture model. In conclusion, we successfully investigated the potential molecular characteristics of M28AP. Full article

(This article belongs to the Special Issue Design and Application of Metal-Binding Proteins)

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Review

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14 pages, 2560 KiB

Open AccessReview

Design of Calcium-Binding Proteins to Sense Calcium

by Shen Tang, Xiaonan Deng, Jie Jiang, Michael Kirberger and Jenny J. Yang

Molecules 2020, 25(9), 2148; https://doi.org/10.3390/molecules25092148 - 4 May 2020

Cited by 14 | Viewed by 5351

Abstract

Calcium controls numerous biological processes by interacting with different classes of calcium binding proteins (CaBP’s), with different affinities, metal selectivities, kinetics, and calcium dependent conformational changes. Due to the diverse coordination chemistry of calcium, and complexity associated with protein folding and binding cooperativity, the rational design of CaBP’s was anticipated to present multiple challenges. In this paper we will first discuss applications of statistical analysis of calcium binding sites in proteins and subsequent development of algorithms to predict and identify calcium binding proteins. Next, we report efforts to identify key determinants for calcium binding affinity, cooperativity and calcium dependent conformational changes using grafting and protein design. Finally, we report recent advances in designing protein calcium sensors to capture calcium dynamics in various cellular environments. Full article

(This article belongs to the Special Issue Design and Application of Metal-Binding Proteins)

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29 pages, 14197 KiB

Open AccessReview

Human Copper-Containing Amine Oxidases in Drug Design and Development

by Serhii Vakal, Sirpa Jalkanen, Käthe M. Dahlström and Tiina A. Salminen

Molecules 2020, 25(6), 1293; https://doi.org/10.3390/molecules25061293 - 12 Mar 2020

Cited by 21 | Viewed by 6071

Abstract

Two members of the copper-containing amine oxidase family are physiologically important proteins: (1) Diamine oxidase (hDAO; AOC1) with a preference for diamines is involved in degradation of histamine and (2) Vascular adhesion protein-1 (hVAP-1; AOC3) with a preference for monoamines is a multifunctional cell-surface receptor and an enzyme. hVAP-1-targeted inhibitors are designed to treat inflammatory diseases and cancer, whereas the off-target binding of the designed inhibitors to hDAO might result in adverse drug reactions. The X-ray structures for both human enzymes are solved and provide the basis for computer-aided inhibitor design, which has been reported by several research groups. Although the putative off-target effect of hDAO is less studied, computational methods could be easily utilized to avoid the binding of VAP-1-targeted inhibitors to hDAO. The choice of the model organism for preclinical testing of hVAP-1 inhibitors is not either trivial due to species-specific binding properties of designed inhibitors and different repertoire of copper-containing amine oxidase family members in mammalian species. Thus, the facts that should be considered in hVAP-1-targeted inhibitor design are discussed in light of the applied structural bioinformatics and structural biology approaches. Full article

(This article belongs to the Special Issue Design and Application of Metal-Binding Proteins)

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18 pages, 3572 KiB

Open AccessReview

Rational Design of Artificial Metalloproteins and Metalloenzymes with Metal Clusters

by Ying-Wu Lin

Molecules 2019, 24(15), 2743; https://doi.org/10.3390/molecules24152743 - 29 Jul 2019

Cited by 29 | Viewed by 7580

Abstract

Metalloproteins and metalloenzymes play important roles in biological systems by using the limited metal ions, complexes, and clusters that are associated with the protein matrix. The design of artificial metalloproteins and metalloenzymes not only reveals the structure and function relationship of natural proteins, but also enables the synthesis of artificial proteins and enzymes with improved properties and functions. Acknowledging the progress in rational design from single to multiple active sites, this review focuses on recent achievements in the design of artificial metalloproteins and metalloenzymes with metal clusters, including zinc clusters, cadmium clusters, iron–sulfur clusters, and copper–sulfur clusters, as well as noble metal clusters and others. These metal clusters were designed in both native and de novo protein scaffolds for structural roles, electron transfer, or catalysis. Some synthetic metal clusters as functional models of native enzymes are also discussed. These achievements provide valuable insights for deep understanding of the natural proteins and enzymes, and practical clues for the further design of artificial enzymes with functions comparable or even beyond those of natural counterparts. Full article

(This article belongs to the Special Issue Design and Application of Metal-Binding Proteins)

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