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Special Issue "Protein Domains: Structures and Molecular Functions"

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

Deadline for manuscript submissions: closed (31 March 2020).

Special Issue Editors

Prof. Dr. Hidekazu Hiroaki
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Guest Editor
Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan
Interests: structural biology; protein structure determination; solution nmr; protein-ligand interaction; intrinsically disordered proteins; protein domain
Dr. Kentaro Tomii
Website
Guest Editor
Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
Interests: bioinformatics; computational biology; structure prediction; structure comparison; sequence analysis; protein domain

Special Issue Information

Dear Colleagues,

Protein domains are modular units in terms of either structural, functional, or evolutionary aspects. After the completion of human genome projects, it was shown that more than 70% of the genes are encoding multidomain proteins with two or more domains. Understanding of structure–function relationships of the individual domains should lead to the illumination new physiological functions of unknown genes. We are motivated by this idea to develop methods for high-throughput structure determination, structure prediction, accurate modelling, molecular dynamic simulation, and the prediction of functions. The accumulation of knowledge of the structure and function of protein domains is still being continued and is providing an important basis for structure-guided drug discovery, protein therapeutics, genome-based diagnosis, designed proteins, molecular beacons and sensors, and synthetic biology. This Special Issue focuses on recent advances in the domain-centric analysis of proteins in the field of biochemistry, bioinformatics and biophysics. In addition, either the analysis of natural domain pairs (architectures) or the design of artificial multi-domain proteins are in focus. Original research papers, concise reviews, and perspectives are welcome.

Prof. Dr. Hidekazu Hiroaki
Dr. Kentaro Tomii
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 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

  • protein domains
  • domain pairs and supra-domains
  • architecture of multi-domain proteins
  • structure determination
  • prediction and modelling
  • simulation
  • database
  • spectroscopic analysis
  • structural comparison
  • folding and stability
  • ligand interaction/molecular recognition
  • dynamics/thermodynamics
  • de novo design
  • domain engineering
  • 3D domain swapping
  • domain selective inhibitors
  • domain-centric interactome
  • domain identification

Published Papers (7 papers)

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Research

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Open AccessArticle
Conserved Dynamic Mechanism of Allosteric Response to L-arg in Divergent Bacterial Arginine Repressors
Molecules 2020, 25(9), 2247; https://doi.org/10.3390/molecules25092247 - 10 May 2020
Abstract
Hexameric arginine repressor, ArgR, is the feedback regulator of bacterial L-arginine regulons, and sensor of L-arg that controls transcription of genes for its synthesis and catabolism. Although ArgR function, as well as its secondary, tertiary, and quaternary structures, is essentially the same in [...] Read more.
Hexameric arginine repressor, ArgR, is the feedback regulator of bacterial L-arginine regulons, and sensor of L-arg that controls transcription of genes for its synthesis and catabolism. Although ArgR function, as well as its secondary, tertiary, and quaternary structures, is essentially the same in E. coli and B. subtilis, the two proteins differ significantly in sequence, including residues implicated in the response to L-arg. Molecular dynamics simulations are used here to evaluate the behavior of intact B. subtilis ArgR with and without L-arg, and are compared with prior MD results for a domain fragment of E. coli ArgR. Relative to its crystal structure, B. subtilis ArgR in absence of L-arg undergoes a large-scale rotational shift of its trimeric subassemblies that is very similar to that observed in the E. coli protein, but the residues driving rotation have distinct secondary and tertiary structural locations, and a key residue that drives rotation in E. coli is missing in B. subtilis. The similarity of trimer rotation despite different driving residues suggests that a rotational shift between trimers is integral to ArgR function. This conclusion is supported by phylogenetic analysis of distant ArgR homologs reported here that indicates at least three major groups characterized by distinct sequence motifs but predicted to undergo a common rotational transition. The dynamic consequences of L-arg binding for transcriptional activation of intact ArgR are evaluated here for the first time in two-microsecond simulations of B. subtilis ArgR. L-arg binding to intact B. subtilis ArgR causes a significant further shift in the angle of rotation between trimers that causes the N-terminal DNA-binding domains lose their interactions with the C-terminal domains, and is likely the first step toward adopting DNA-binding-competent conformations. The results aid interpretation of crystal structures of ArgR and ArgR-DNA complexes. Full article
(This article belongs to the Special Issue Protein Domains: Structures and Molecular Functions)
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Open AccessArticle
Investigation of the Relationship between the S1 Domain and Its Molecular Functions Derived from Studies of the Tertiary Structure
Molecules 2019, 24(20), 3681; https://doi.org/10.3390/molecules24203681 - 13 Oct 2019
Abstract
S1 domain, a structural variant of one of the “oldest” OB-folds (oligonucleotide/oligosaccharide-binding fold), is widespread in various proteins in three domains of life: Bacteria, Eukaryotes, and Archaea. In this study, it was shown that S1 domains of bacterial, eukaryotic, and archaeal proteins have [...] Read more.
S1 domain, a structural variant of one of the “oldest” OB-folds (oligonucleotide/oligosaccharide-binding fold), is widespread in various proteins in three domains of life: Bacteria, Eukaryotes, and Archaea. In this study, it was shown that S1 domains of bacterial, eukaryotic, and archaeal proteins have a low percentage of identity, which indicates the uniqueness of the scaffold and is associated with protein functions. Assessment of the predisposition of tertiary flexibility of S1 domains using computational and statistical tools showed similar structural features and revealed functional flexible regions that are potentially involved in the interaction of natural binding partners. In addition, we analyzed the relative number and distribution of S1 domains in all domains of life and established specific features based on sequences and structures associated with molecular functions. The results correlate with the presence of repeats of the S1 domain in proteins containing the S1 domain in the range from one (bacterial and archaeal) to 15 (eukaryotic) and, apparently, are associated with the need for individual proteins to increase the affinity and specificity of protein binding to ligands. Full article
(This article belongs to the Special Issue Protein Domains: Structures and Molecular Functions)
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Open AccessArticle
Crystal Structure of Human EOLA1 Implies Its Possibility of RNA Binding
Molecules 2019, 24(19), 3529; https://doi.org/10.3390/molecules24193529 - 29 Sep 2019
Abstract
Human endothelial-overexpressed lipopolysaccharide-associated factor 1 (EOLA1) has been suggested to regulate inflammatory responses in endothelial cells by controlling expression of proteins, interleukin-6 and vascular cell adhesion molecule-1, and by preventing apoptosis. To elucidate the structural basis of the EOLA1 function, we determined its [...] Read more.
Human endothelial-overexpressed lipopolysaccharide-associated factor 1 (EOLA1) has been suggested to regulate inflammatory responses in endothelial cells by controlling expression of proteins, interleukin-6 and vascular cell adhesion molecule-1, and by preventing apoptosis. To elucidate the structural basis of the EOLA1 function, we determined its crystal structure at 1.71 Å resolution and found that EOLA1 is structurally similar to an activating signal cointegrator-1 homology (ASCH) domain with a characteristic β-barrel fold surrounded by α-helices. Despite its low sequence identity with other ASCH domains, EOLA1 retains a conserved ‘GxKxxExR’ motif in its cavity structure. The cavity harbors aromatic and polar residues, which are speculated to accommodate nucleotide molecules as do YT521-B homology (YTH) proteins. Additionally, EOLA1 exhibits a positively charged cleft, similar to those observed in YTH proteins and the ASCH protein from Zymomonas mobilis that exerts ribonuclease activity. This implies that the positively charged cleft in EOLA1 could stabilize the binding of RNA molecules. Taken together, we suggest that EOLA1 controls protein expression through RNA binding to play protective roles against endothelial cell injuries resulting from lipopolysaccharide (LPS)-induced inflammation responses. Full article
(This article belongs to the Special Issue Protein Domains: Structures and Molecular Functions)
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Open AccessArticle
Structural and Aggregation Features of a Human κ-Casein Fragment with Antitumor and Cell-Penetrating Properties
Molecules 2019, 24(16), 2919; https://doi.org/10.3390/molecules24162919 - 12 Aug 2019
Abstract
Intrinsically disordered proteins play a central role in dynamic regulatory and assembly processes in the cell. Recently, a human κ-casein proteolytic fragment called lactaptin (8.6 kDa) was found to induce apoptosis of human breast adenocarcinoma MCF-7 and MDA-MB-231 cells with no cytotoxic activity [...] Read more.
Intrinsically disordered proteins play a central role in dynamic regulatory and assembly processes in the cell. Recently, a human κ-casein proteolytic fragment called lactaptin (8.6 kDa) was found to induce apoptosis of human breast adenocarcinoma MCF-7 and MDA-MB-231 cells with no cytotoxic activity toward normal cells. Earlier, we had designed some recombinant analogs of lactaptin and compared their biological activity. Among these analogs, RL2 has the highest antitumor activity, but the amino acid residues and secondary structures that are responsible for RL2′s activity remain unclear. To elucidate the structure–activity relations of RL2, we studied the structural and aggregation features of this fairly large intrinsically disordered fragment of human milk κ-casein by a combination of physicochemical methods: NMR, paramagnetic relaxation enhancement (PRE), Electron Paramagnetic Resonance (EPR), circular dichroism, dynamic light scattering, atomic force microscopy, and a cytotoxic activity assay. It was found that in solution, RL2 exists as stand-alone monomeric particles and large aggregates. Whereas the disulfide-bonded homodimer turned out to be more prone to assembly into large aggregates, the monomer predominantly forms single particles. NMR relaxation analysis of spin-labeled RL2 showed that the RL2 N-terminal region, which is essential not only for multimerization of the peptide but also for its proapoptotic action on cancer cells, is more ordered than its C-terminal counterpart and contains a site with a propensity for α-helical secondary structure. Full article
(This article belongs to the Special Issue Protein Domains: Structures and Molecular Functions)
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Open AccessArticle
Cyclization of Single-Chain Fv Antibodies Markedly Suppressed Their Characteristic Aggregation Mediated by Inter-Chain VH-VL Interactions
Molecules 2019, 24(14), 2620; https://doi.org/10.3390/molecules24142620 - 18 Jul 2019
Cited by 3
Abstract
Single-chain Fv (scFv) antibodies are recombinant proteins in which the variable regions of the heavy chain (VH) and light chain (VL) are connected by a short flexible polypeptide linker. ScFvs have the advantages of easy genetic manipulation and low-cost production using Escherichia coli [...] Read more.
Single-chain Fv (scFv) antibodies are recombinant proteins in which the variable regions of the heavy chain (VH) and light chain (VL) are connected by a short flexible polypeptide linker. ScFvs have the advantages of easy genetic manipulation and low-cost production using Escherichia coli compared with monoclonal antibodies, and are thus expected to be utilized as next-generation medical antibodies. However, the practical use of scFvs has been limited due to low homogeneity caused by their aggregation propensity mediated by inter-chain VH-VL interactions. Because the interactions between the VH and VL domains of antibodies are generally weak, individual scFvs are assumed to be in equilibrium between a closed state and an open state, in which the VH and VL domains are assembled and disassembled, respectively. This dynamic feature of scFvs triggers the formation of dimer, trimer, and larger aggregates caused by the inter-chain VH-VL interactions. To overcome this problem, the N-terminus and C-terminus were herein connected by sortase A-mediated ligation to produce a cyclic scFv. Open-closed dynamics and aggregation were markedly suppressed in the cyclic scFv, as judged from dynamic light scattering and high-speed atomic force microscopy analyses. Surface plasmon resonance and differential scanning fluorometry analysis revealed that neither the affinity for antigen nor the thermal stability was disrupted by the scFv cyclization. Generality was confirmed by applying the present method to several scFv proteins. Based on these results, cyclic scFvs are expected to be widely utilized in industrial and therapeutic applications. Full article
(This article belongs to the Special Issue Protein Domains: Structures and Molecular Functions)
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Review

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Open AccessFeature PaperReview
Advances in Structure Modeling Methods for Cryo-Electron Microscopy Maps
Molecules 2020, 25(1), 82; https://doi.org/10.3390/molecules25010082 - 24 Dec 2019
Abstract
Cryo-electron microscopy (cryo-EM) has now become a widely used technique for structure determination of macromolecular complexes. For modeling molecular structures from density maps of different resolutions, many algorithms have been developed. These algorithms can be categorized into rigid fitting, flexible fitting, and de [...] Read more.
Cryo-electron microscopy (cryo-EM) has now become a widely used technique for structure determination of macromolecular complexes. For modeling molecular structures from density maps of different resolutions, many algorithms have been developed. These algorithms can be categorized into rigid fitting, flexible fitting, and de novo modeling methods. It is also observed that machine learning (ML) techniques have been increasingly applied following the rapid progress of the ML field. Here, we review these different categories of macromolecule structure modeling methods and discuss their advances over time. Full article
(This article belongs to the Special Issue Protein Domains: Structures and Molecular Functions)
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Open AccessReview
Activity and Affinity of Pin1 Variants
Molecules 2020, 25(1), 36; https://doi.org/10.3390/molecules25010036 - 20 Dec 2019
Abstract
Pin1 is a peptidyl-prolyl isomerase responsible for isomerizing phosphorylated S/T-P motifs. Pin1 has two domains that each have a distinct ligand binding site, but only its PPIase domain has catalytic activity. Vast evidence supports interdomain allostery of Pin1, with binding of a ligand [...] Read more.
Pin1 is a peptidyl-prolyl isomerase responsible for isomerizing phosphorylated S/T-P motifs. Pin1 has two domains that each have a distinct ligand binding site, but only its PPIase domain has catalytic activity. Vast evidence supports interdomain allostery of Pin1, with binding of a ligand to its regulatory WW domain impacting activity in the PPIase domain. Many diverse studies have made mutations in Pin1 in order to elucidate interactions that are responsible for ligand binding, isomerase activity, and interdomain allostery. Here, we summarize these mutations and their impact on Pin1′s structure and function. Full article
(This article belongs to the Special Issue Protein Domains: Structures and Molecular Functions)
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