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Frontiers in Protein Structure Research

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 (28 November 2021) | Viewed by 68856

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Guest Editor
1. Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, 1117 Budapest, Hungary
2. Center of Excellence of the Hungarian Academy of Sciences, 1117 Budapest, Hungary
Interests: protein structures; protein dynamics; protein conformation; protein folding; protein bioinformatics; protein interactions; membrane proteins; protein stability; intrinsically disordered proteins; protein biophysics; protein binding; molecular biophysics; protein refolding; membrane transport proteins; computational structural biology; structural bioinformatics
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Guest Editor
Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, Hungary
Interests: protein bioinformatics; protein stability; intrinsically disordered proteins; protein structure; protein structure modeling; protein dynamics; molecular dynamics simulation; protein conformation; computational structural biology; structural bioinformatics; drug design; structure based drug design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, new frontiers opened in protein structure research. Besides the traditional form of proteins, like folded water soluble proteins, transmembrane and membrane associated proteins, disordered proteins which able to fold on the surface of folded proteins or other stable macromolecules, new forms of proteins and protein complexes emerged. Among others, fuzzy complexes in which during physiological function at least one protein component is still in disordered form, mutual synergistic folding complexes in which two or more disordered proteins help each-other to fold, are new subclasses of proteins. Combination of the above mentioned proteins, like partially disordered proteins or proteins participating in liquid-liquid phase separation, represent new forms of proteins. These are all new and interesting fields of proteins structure research.

As guest editors of the “Frontiers in protein structure” special issue of IJMS, we would like to invite you to contribute a paper related to protein structures.

Prof. Dr. Istvan Simon
Dr. Csaba Magyar
Guest Editors

Manuscript Submission Information

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Keywords

  • fuzzy complexes
  • intrinsically disordered proteins
  • liquid-liquid phase separation
  • mutual synergistic folding
  • protein dynamics
  • protein folding
  • protein structure
  • protein-protein interactions
  • transmembrane proteins

Published Papers (23 papers)

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8 pages, 242 KiB  
Editorial
Assortment of Frontiers in Protein Science
by István Simon and Csaba Magyar
Int. J. Mol. Sci. 2022, 23(7), 3685; https://doi.org/10.3390/ijms23073685 - 28 Mar 2022
Viewed by 1342
Abstract
Recent decades have brought significant changes to the protein structure research field [...] Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)

Research

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20 pages, 4785 KiB  
Article
Pyranose Ring Puckering Thermodynamics for Glycan Monosaccharides Associated with Vertebrate Proteins
by Olgun Guvench, Devon Martin and Megan Greene
Int. J. Mol. Sci. 2022, 23(1), 473; https://doi.org/10.3390/ijms23010473 - 31 Dec 2021
Cited by 9 | Viewed by 2514
Abstract
The conformational properties of carbohydrates can contribute to protein structure directly through covalent conjugation in the cases of glycoproteins and proteoglycans and indirectly in the case of transmembrane proteins embedded in glycolipid-containing bilayers. However, there continue to be significant challenges associated with experimental [...] Read more.
The conformational properties of carbohydrates can contribute to protein structure directly through covalent conjugation in the cases of glycoproteins and proteoglycans and indirectly in the case of transmembrane proteins embedded in glycolipid-containing bilayers. However, there continue to be significant challenges associated with experimental structural biology of such carbohydrate-containing systems. All-atom explicit-solvent molecular dynamics simulations provide a direct atomic resolution view of biomolecular dynamics and thermodynamics, but the accuracy of the results depends on the quality of the force field parametrization used in the simulations. A key determinant of the conformational properties of carbohydrates is ring puckering. Here, we applied extended system adaptive biasing force (eABF) all-atom explicit-solvent molecular dynamics simulations to characterize the ring puckering thermodynamics of the ten common pyranose monosaccharides found in vertebrate biology (as represented by the CHARMM carbohydrate force field). The results, along with those for idose, demonstrate that the CHARMM force field reliably models ring puckering across this diverse set of molecules, including accurately capturing the subtle balance between 4C1 and 1C4 chair conformations in the cases of iduronate and of idose. This suggests the broad applicability of the force field for accurate modeling of carbohydrate-containing vertebrate biomolecules such as glycoproteins, proteoglycans, and glycolipids. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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10 pages, 2830 KiB  
Article
Origin of Increased Solvent Accessibility of Peptide Bonds in Mutual Synergetic Folding Proteins
by Csaba Magyar, Anikó Mentes, Miklós Cserző and István Simon
Int. J. Mol. Sci. 2021, 22(24), 13404; https://doi.org/10.3390/ijms222413404 - 14 Dec 2021
Cited by 2 | Viewed by 1927
Abstract
Mutual Synergetic Folding (MSF) proteins belong to a recently discovered class of proteins. These proteins are disordered in their monomeric but ordered in their oligomeric forms. Their amino acid composition is more similar to globular proteins than to disordered ones. Our preceding work [...] Read more.
Mutual Synergetic Folding (MSF) proteins belong to a recently discovered class of proteins. These proteins are disordered in their monomeric but ordered in their oligomeric forms. Their amino acid composition is more similar to globular proteins than to disordered ones. Our preceding work shed light on important structural aspects of the structural organization of these proteins, but the background of this behavior is still unknown. We suggest that solvent accessibility is an important factor, especially solvent accessibility of the peptide bonds can be accounted for this phenomenon. The side chains of the amino acids which form a peptide bond have a high local contribution to the shielding of the peptide bond from the solvent. During the oligomerization step, other non-local residues contribute to the shielding. We investigated these local and non-local effects of shielding based on Shannon information entropy calculations. We found that MSF and globular homodimeric proteins have different local contributions resulting from different amino acid pair frequencies. Their non-local distribution is also different because of distinctive inter-subunit contacts. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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10 pages, 1342 KiB  
Article
Evaluation of Deep Neural Network ProSPr for Accurate Protein Distance Predictions on CASP14 Targets
by Jacob Stern, Bryce Hedelius, Olivia Fisher, Wendy M. Billings and Dennis Della Corte
Int. J. Mol. Sci. 2021, 22(23), 12835; https://doi.org/10.3390/ijms222312835 - 27 Nov 2021
Cited by 8 | Viewed by 2458
Abstract
The field of protein structure prediction has recently been revolutionized through the introduction of deep learning. The current state-of-the-art tool AlphaFold2 can predict highly accurate structures; however, it has a prohibitively long inference time for applications that require the folding of hundreds of [...] Read more.
The field of protein structure prediction has recently been revolutionized through the introduction of deep learning. The current state-of-the-art tool AlphaFold2 can predict highly accurate structures; however, it has a prohibitively long inference time for applications that require the folding of hundreds of sequences. The prediction of protein structure annotations, such as amino acid distances, can be achieved at a higher speed with existing tools, such as the ProSPr network. Here, we report on important updates to the ProSPr network, its performance in the recent Critical Assessment of Techniques for Protein Structure Prediction (CASP14) competition, and an evaluation of its accuracy dependency on sequence length and multiple sequence alignment depth. We also provide a detailed description of the architecture and the training process, accompanied by reusable code. This work is anticipated to provide a solid foundation for the further development of protein distance prediction tools. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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7 pages, 1052 KiB  
Communication
MemDis: Predicting Disordered Regions in Transmembrane Proteins
by Laszlo Dobson and Gábor E. Tusnády
Int. J. Mol. Sci. 2021, 22(22), 12270; https://doi.org/10.3390/ijms222212270 - 12 Nov 2021
Cited by 12 | Viewed by 1780
Abstract
Transmembrane proteins (TMPs) play important roles in cells, ranging from transport processes and cell adhesion to communication. Many of these functions are mediated by intrinsically disordered regions (IDRs), flexible protein segments without a well-defined structure. Although a variety of prediction methods are available [...] Read more.
Transmembrane proteins (TMPs) play important roles in cells, ranging from transport processes and cell adhesion to communication. Many of these functions are mediated by intrinsically disordered regions (IDRs), flexible protein segments without a well-defined structure. Although a variety of prediction methods are available for predicting IDRs, their accuracy is very limited on TMPs due to their special physico-chemical properties. We prepared a dataset containing membrane proteins exclusively, using X-ray crystallography data. MemDis is a novel prediction method, utilizing convolutional neural network and long short-term memory networks for predicting disordered regions in TMPs. In addition to attributes commonly used in IDR predictors, we defined several TMP specific features to enhance the accuracy of our method further. MemDis achieved the highest prediction accuracy on TMP-specific dataset among other popular IDR prediction methods. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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20 pages, 5649 KiB  
Article
The Effect of Multisite Phosphorylation on the Conformational Properties of Intrinsically Disordered Proteins
by Ellen Rieloff and Marie Skepö
Int. J. Mol. Sci. 2021, 22(20), 11058; https://doi.org/10.3390/ijms222011058 - 14 Oct 2021
Cited by 12 | Viewed by 2180
Abstract
Intrinsically disordered proteins are involved in many biological processes such as signaling, regulation, and recognition. A common strategy to regulate their function is through phosphorylation, as it can induce changes in conformation, dynamics, and interactions with binding partners. Although phosphorylated intrinsically disordered proteins [...] Read more.
Intrinsically disordered proteins are involved in many biological processes such as signaling, regulation, and recognition. A common strategy to regulate their function is through phosphorylation, as it can induce changes in conformation, dynamics, and interactions with binding partners. Although phosphorylated intrinsically disordered proteins have received increased attention in recent years, a full understanding of the conformational and structural implications of phosphorylation has not yet been achieved. Here, we present all-atom molecular dynamics simulations of five disordered peptides originated from tau, statherin, and β-casein, in both phosphorylated and non-phosphorylated state, to compare changes in global dimensions and structural elements, in an attempt to gain more insight into the controlling factors. The changes are in qualitative agreement with experimental data, and we observe that the net charge is not enough to predict the impact of phosphorylation on the global dimensions. Instead, the distribution of phosphorylated and positively charged residues throughout the sequence has great impact due to the formation of salt bridges. In statherin, a preference for arginine–phosphoserine interaction over arginine–tyrosine accounts for a global expansion, despite a local contraction of the phosphorylated region, which implies that also non-charged residues can influence the effect of phosphorylation. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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18 pages, 1239 KiB  
Article
Saturation Mutagenesis of the Transmembrane Region of HokC in Escherichia coli Reveals Its High Tolerance to Mutations
by Maria Teresa Lara Ortiz, Victor Martinell García and Gabriel Del Rio
Int. J. Mol. Sci. 2021, 22(19), 10359; https://doi.org/10.3390/ijms221910359 - 26 Sep 2021
Cited by 1 | Viewed by 2216
Abstract
Cells adapt to different stress conditions, such as the antibiotics presence. This adaptation sometimes is achieved by changing relevant protein positions, of which the mutability is limited by structural constrains. Understanding the basis of these constrains represent an important challenge for both basic [...] Read more.
Cells adapt to different stress conditions, such as the antibiotics presence. This adaptation sometimes is achieved by changing relevant protein positions, of which the mutability is limited by structural constrains. Understanding the basis of these constrains represent an important challenge for both basic science and potential biotechnological applications. To study these constraints, we performed a systematic saturation mutagenesis of the transmembrane region of HokC, a toxin used by Escherichia coli to control its own population, and observed that 92% of single-point mutations are tolerated and that all the non-tolerated mutations have compensatory mutations that reverse their effect. We provide experimental evidence that HokC accumulates multiple compensatory mutations that are found as correlated mutations in the HokC family multiple sequence alignment. In agreement with these observations, transmembrane proteins show higher probability to present correlated mutations and are less densely packed locally than globular proteins; previous mutagenesis results on transmembrane proteins further support our observations on the high tolerability to mutations of transmembrane regions of proteins. Thus, our experimental results reveal the HokC transmembrane region high tolerance to loss-of-function mutations that is associated with low sequence conservation and high rate of correlated mutations in the HokC family sequences alignment, which are features shared with other transmembrane proteins. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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17 pages, 13097 KiB  
Article
Molecular Dynamics Simulations of Phosphorylated Intrinsically Disordered Proteins: A Force Field Comparison
by Ellen Rieloff and Marie Skepö
Int. J. Mol. Sci. 2021, 22(18), 10174; https://doi.org/10.3390/ijms221810174 - 21 Sep 2021
Cited by 14 | Viewed by 3847
Abstract
Phosphorylation is a common post-translational modification among intrinsically disordered proteins and regions, which helps regulate function by changing the protein conformations, dynamics, and interactions with binding partners. To fully comprehend the effects of phosphorylation, computer simulations are a helpful tool, although they are [...] Read more.
Phosphorylation is a common post-translational modification among intrinsically disordered proteins and regions, which helps regulate function by changing the protein conformations, dynamics, and interactions with binding partners. To fully comprehend the effects of phosphorylation, computer simulations are a helpful tool, although they are dependent on the accuracy of the force field used. Here, we compared the conformational ensembles produced by Amber ff99SB-ILDN+TIP4P-D and CHARMM36m, for four phosphorylated disordered peptides ranging in length from 14–43 residues. CHARMM36m consistently produced more compact conformations with a higher content of bends, mainly due to more stable salt bridges. Based on comparisons with experimental size estimates for the shortest and longest peptide, CHARMM36m appeared to overestimate the compactness. The difference between the force fields was largest for the peptide showing the greatest separation between positively charged and phosphorylated residues, in line with the importance of charge distribution. For this peptide, the conformational ensemble did not change significantly upon increasing the ionic strength from 0 mM to 150 mM, despite a reduction of the salt-bridging probability in the CHARMM36m simulations, implying that salt concentration has negligible effects in this study. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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18 pages, 3070 KiB  
Article
Fenton-Chemistry-Based Oxidative Modification of Proteins Reflects Their Conformation
by Thomas Nehls, Tim Heymann, Christian Meyners, Felix Hausch and Frederik Lermyte
Int. J. Mol. Sci. 2021, 22(18), 9927; https://doi.org/10.3390/ijms22189927 - 14 Sep 2021
Cited by 6 | Viewed by 2795
Abstract
In order to understand protein structure to a sufficient extent for, e.g., drug discovery, no single technique can provide satisfactory information on both the lowest-energy conformation and on dynamic changes over time (the ‘four-dimensional’ protein structure). Instead, a combination of complementary techniques is [...] Read more.
In order to understand protein structure to a sufficient extent for, e.g., drug discovery, no single technique can provide satisfactory information on both the lowest-energy conformation and on dynamic changes over time (the ‘four-dimensional’ protein structure). Instead, a combination of complementary techniques is required. Mass spectrometry methods have shown promise in addressing protein dynamics, but often rely on the use of high-end commercial or custom instruments. Here, we apply well-established chemistry to conformation-sensitive oxidative protein labelling on a timescale of a few seconds, followed by analysis through a routine protein analysis workflow. For a set of model proteins, we show that site selectivity of labelling can indeed be rationalised in terms of known structural information, and that conformational changes induced by ligand binding are reflected in the modification pattern. In addition to conventional bottom-up analysis, further insights are obtained from intact mass measurement and native mass spectrometry. We believe that this method will provide a valuable and robust addition to the ‘toolbox’ of mass spectrometry researchers studying higher-order protein structure. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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18 pages, 19125 KiB  
Article
An In Vitro Comparative Study of the Effects of Tetrabromobisphenol A and Tetrabromobisphenol S on Human Erythrocyte Membranes—Changes in ATP Level, Perturbations in Membrane Fluidity, Alterations in Conformational State and Damage to Proteins
by Monika Jarosiewicz, Piotr Duchnowicz, Paweł Jarosiewicz, Bogumiła Huras and Bożena Bukowska
Int. J. Mol. Sci. 2021, 22(17), 9443; https://doi.org/10.3390/ijms22179443 - 31 Aug 2021
Cited by 7 | Viewed by 1911
Abstract
Brominated flame retardants (BFRs) are substances used to reduce the flammability of plastics. Among this group, tetrabormobisphenol A (TBBPA) is currently produced and used on the greatest scale, but due to the emerging reports on its potential toxicity, tetrabromobisphenol S (TBBPS)—a compound with [...] Read more.
Brominated flame retardants (BFRs) are substances used to reduce the flammability of plastics. Among this group, tetrabormobisphenol A (TBBPA) is currently produced and used on the greatest scale, but due to the emerging reports on its potential toxicity, tetrabromobisphenol S (TBBPS)—a compound with a very similar structure—is used as an alternative. Due to the fact that the compounds in question are found in the environment and in biological samples from living organisms, including humans, and due to the insufficient toxicological knowledge about them, it is necessary to assess their impacts on living organisms and verify the validity of TBBPA replacement by TBBPS. The RBC membrane was chosen as the research model. This is a widely accepted research model for assessing the toxicity of xenobiotics, and it is the first barrier to compounds entering circulation. It was found that TBBPA and TBBPS caused increases in the fluidity of the erythrocyte membrane in their hydrophilic layer, and conformational changes to membrane proteins. They also caused thiol group elevation, an increase in lipid peroxidation (TBBPS only) and decreases in the level of ATP in cells. They also caused changes in the size and shape of RBCs. TBBPA caused changes in the erythrocyte membrane at lower concentrations compared to TBBPS at an occupational exposure level. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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12 pages, 3616 KiB  
Article
Possible Link between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity
by Vipul Kumar, Jasdeep Singh, Seyed E. Hasnain and Durai Sundar
Int. J. Mol. Sci. 2021, 22(17), 9131; https://doi.org/10.3390/ijms22179131 - 24 Aug 2021
Cited by 59 | Viewed by 5308
Abstract
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has created alarming situations worldwide and is being attributed to the false negativity in RT-PCR tests. It has also [...] Read more.
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has created alarming situations worldwide and is being attributed to the false negativity in RT-PCR tests. It has also increased the chances of reinfection and immune escape. Recently various lineages namely, B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.617.3 have caused rapid infection around the globe. To understand the biophysical perspective, we have performed molecular dynamic simulations of four different spikes (receptor binding domain)-hACE2 complexes, namely wildtype (WT), Alpha variant (N501Y spike mutant), Kappa (L452R, E484Q) and Delta (L452R, T478K), and compared their dynamics, binding energy and molecular interactions. Our results show that mutation has caused significant increase in the binding energy between the spike and hACE2 in Alpha and Kappa variants. In the case of Kappa and Delta variants, the mutations at L452R, T478K and E484Q increased the stability and intra-chain interactions in the spike protein, which may change the interaction ability of neutralizing antibodies to these spike variants. Further, we found that the Alpha variant had increased hydrogen interaction with Lys353 of hACE2 and more binding affinity in comparison to WT. The current study provides the biophysical basis for understanding the molecular mechanism and rationale behind the increase in the transmissivity and infectivity of the mutants compared to wild-type SARS-CoV-2. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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18 pages, 13124 KiB  
Article
Natural Mutations Affect Structure and Function of gC1q Domain of Otolin-1
by Rafał Hołubowicz, Andrzej Ożyhar and Piotr Dobryszycki
Int. J. Mol. Sci. 2021, 22(16), 9085; https://doi.org/10.3390/ijms22169085 - 23 Aug 2021
Cited by 6 | Viewed by 2237
Abstract
Otolin-1 is a scaffold protein of otoliths and otoconia, calcium carbonate biominerals from the inner ear. It contains a gC1q domain responsible for trimerization and binding of Ca2+. Knowledge of a structure–function relationship of gC1q domain of otolin-1 is crucial for [...] Read more.
Otolin-1 is a scaffold protein of otoliths and otoconia, calcium carbonate biominerals from the inner ear. It contains a gC1q domain responsible for trimerization and binding of Ca2+. Knowledge of a structure–function relationship of gC1q domain of otolin-1 is crucial for understanding the biology of balance sensing. Here, we show how natural variants alter the structure of gC1q otolin-1 and how Ca2+ are able to revert some effects of the mutations. We discovered that natural substitutions: R339S, R342W and R402P negatively affect the stability of apo-gC1q otolin-1, and that Q426R has a stabilizing effect. In the presence of Ca2+, R342W and Q426R were stabilized at higher Ca2+ concentrations than the wild-type form, and R402P was completely insensitive to Ca2+. The mutations affected the self-association of gC1q otolin-1 by inducing detrimental aggregation (R342W) or disabling the trimerization (R402P) of the protein. Our results indicate that the natural variants of gC1q otolin-1 may have a potential to cause pathological changes in otoconia and otoconial membrane, which could affect sensing of balance and increase the probability of occurrence of benign paroxysmal positional vertigo (BPPV). Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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18 pages, 5707 KiB  
Article
Structural Contour Map of the Iota Carbonic Anhydrase from the Diatom Thalassiosira pseudonana Using a Multiprong Approach
by Erik L. Jensen, Véronique Receveur-Brechot, Mohand Hachemane, Laura Wils, Pascale Barbier, Goetz Parsiegla, Brigitte Gontero and Hélène Launay
Int. J. Mol. Sci. 2021, 22(16), 8723; https://doi.org/10.3390/ijms22168723 - 13 Aug 2021
Cited by 9 | Viewed by 2487
Abstract
Carbonic anhydrases (CAs) are a family of ubiquitous enzymes that catalyze the interconversion of CO2 and HCO3. The “iota” class (ι-CA) was first found in the marine diatom Thalassiosira pseudonana (tpι-CA) and is widespread among photosynthetic microalgae and prokaryotes. [...] Read more.
Carbonic anhydrases (CAs) are a family of ubiquitous enzymes that catalyze the interconversion of CO2 and HCO3. The “iota” class (ι-CA) was first found in the marine diatom Thalassiosira pseudonana (tpι-CA) and is widespread among photosynthetic microalgae and prokaryotes. The ι-CA has a domain COG4875 (or COG4337) that can be repeated from one to several times and resembles a calcium–calmodulin protein kinase II association domain (CaMKII-AD). The crystal structure of this domain in the ι-CA from a cyanobacterium and a chlorarachniophyte has been recently determined. However, the three-dimensional organization of the four domain-containing tpι-CA is unknown. Using biophysical techniques and 3-D modeling, we show that the homotetrameric tpι-CA in solution has a flat “drone-like” shape with a core formed by the association of the first two domains of each monomer, and four protruding arms formed by domains 3 and 4. We also observe that the short linker between domains 3 and 4 in each monomer confers high flexibility, allowing for different conformations to be adopted. We propose the possible 3-D structure of a truncated tpι-CA containing fewer domain repeats using experimental data and discuss the implications of this atypical shape on the activity and metal coordination of the ι-CA. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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15 pages, 2064 KiB  
Article
Architecture Insight of Bifidobacterial α-L-Fucosidases
by José Antonio Curiel, Ángela Peirotén, José María Landete, Ana Ruiz de la Bastida, Susana Langa and Juan Luis Arqués
Int. J. Mol. Sci. 2021, 22(16), 8462; https://doi.org/10.3390/ijms22168462 - 6 Aug 2021
Cited by 7 | Viewed by 5042
Abstract
Fucosylated carbohydrates and glycoproteins from human breast milk are essential for the development of the gut microbiota in early life because they are selectively metabolized by bifidobacteria. In this regard, α-L-fucosidases play a key role in this successful bifidobacterial colonization allowing the utilization [...] Read more.
Fucosylated carbohydrates and glycoproteins from human breast milk are essential for the development of the gut microbiota in early life because they are selectively metabolized by bifidobacteria. In this regard, α-L-fucosidases play a key role in this successful bifidobacterial colonization allowing the utilization of these substrates. Although a considerable number of α-L-fucosidases from bifidobacteria have been identified by computational analysis, only a few of them have been characterized. Hitherto, α-L-fucosidases are classified into three families: GH29, GH95, and GH151, based on their catalytic structure. However, bifidobacterial α-L-fucosidases belonging to a particular family show significant differences in their sequence. Because this fact could underlie distinct phylogenetic evolution, here extensive similarity searches and comparative analyses of the bifidobacterial α-L-fucosidases identified were carried out with the assistance of previous physicochemical studies available. This work reveals four and two paralogue bifidobacterial fucosidase groups within GH29 and GH95 families, respectively. Moreover, Bifidobacterium longum subsp. infantis species exhibited the greatest number of phylogenetic lineages in their fucosidases clustered in every family: GH29, GH95, and GH151. Since α-L-fucosidases phylogenetically descended from other glycosyl hydrolase families, we hypothesized that they could exhibit additional glycosidase activities other than fucosidase, raising the possibility of their application to transfucosylate substrates other than lactose in order to synthesis novel prebiotics. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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16 pages, 2630 KiB  
Article
Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered
by Nadun C. Karunatilleke, Courtney S. Fast, Vy Ngo, Anne Brickenden, Martin L. Duennwald, Lars Konermann and Wing-Yiu Choy
Int. J. Mol. Sci. 2021, 22(14), 7434; https://doi.org/10.3390/ijms22147434 - 11 Jul 2021
Cited by 22 | Viewed by 4452
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription regulator that plays a pivotal role in coordinating the cellular response to oxidative stress. Through interactions with other proteins, such as Kelch-like ECH-associated protein 1 (Keap1), CREB-binding protein (CBP), and retinoid X receptor [...] Read more.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription regulator that plays a pivotal role in coordinating the cellular response to oxidative stress. Through interactions with other proteins, such as Kelch-like ECH-associated protein 1 (Keap1), CREB-binding protein (CBP), and retinoid X receptor alpha (RXRα), Nrf2 mediates the transcription of cytoprotective genes critical for removing toxicants and preventing DNA damage, thereby playing a significant role in chemoprevention. Dysregulation of Nrf2 is linked to tumorigenesis and chemoresistance, making Nrf2 a promising target for anticancer therapeutics. However, despite the physiological importance of Nrf2, the molecular details of this protein and its interactions with most of its targets remain unknown, hindering the rational design of Nrf2-targeted therapeutics. With this in mind, we used a combined bioinformatics and experimental approach to characterize the structure of full-length Nrf2 and its interaction with Keap1. Our results show that Nrf2 is partially disordered, with transiently structured elements in its Neh2, Neh7, and Neh1 domains. Moreover, interaction with the Kelch domain of Keap1 leads to protection of the binding motifs in the Neh2 domain of Nrf2, while the rest of the protein remains highly dynamic. This work represents the first detailed structural characterization of full-length Nrf2 and provides valuable insights into the molecular basis of Nrf2 activity modulation in oxidative stress response. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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19 pages, 6357 KiB  
Article
A Concerted Action of UBA5 C-Terminal Unstructured Regions Is Important for Transfer of Activated UFM1 to UFC1
by Nicole Wesch, Frank Löhr, Natalia Rogova, Volker Dötsch and Vladimir V. Rogov
Int. J. Mol. Sci. 2021, 22(14), 7390; https://doi.org/10.3390/ijms22147390 - 9 Jul 2021
Cited by 7 | Viewed by 2757
Abstract
Ubiquitin fold modifier 1 (UFM1) is a member of the ubiquitin-like protein family. UFM1 undergoes a cascade of enzymatic reactions including activation by UBA5 (E1), transfer to UFC1 (E2) and selective conjugation to a number of target proteins via UFL1 (E3) enzymes. Despite [...] Read more.
Ubiquitin fold modifier 1 (UFM1) is a member of the ubiquitin-like protein family. UFM1 undergoes a cascade of enzymatic reactions including activation by UBA5 (E1), transfer to UFC1 (E2) and selective conjugation to a number of target proteins via UFL1 (E3) enzymes. Despite the importance of ufmylation in a variety of cellular processes and its role in the pathogenicity of many human diseases, the molecular mechanisms of the ufmylation cascade remains unclear. In this study we focused on the biophysical and biochemical characterization of the interaction between UBA5 and UFC1. We explored the hypothesis that the unstructured C-terminal region of UBA5 serves as a regulatory region, controlling cellular localization of the elements of the ufmylation cascade and effective interaction between them. We found that the last 20 residues in UBA5 are pivotal for binding to UFC1 and can accelerate the transfer of UFM1 to UFC1. We solved the structure of a complex of UFC1 and a peptide spanning the last 20 residues of UBA5 by NMR spectroscopy. This structure in combination with additional NMR titration and isothermal titration calorimetry experiments revealed the mechanism of interaction and confirmed the importance of the C-terminal unstructured region in UBA5 for the ufmylation cascade. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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15 pages, 3290 KiB  
Article
Protein–Protein Docking with Large-Scale Backbone Flexibility Using Coarse-Grained Monte-Carlo Simulations
by Mateusz Kurcinski, Sebastian Kmiecik, Mateusz Zalewski and Andrzej Kolinski
Int. J. Mol. Sci. 2021, 22(14), 7341; https://doi.org/10.3390/ijms22147341 - 8 Jul 2021
Cited by 5 | Viewed by 3323
Abstract
Most of the protein–protein docking methods treat proteins as almost rigid objects. Only the side-chains flexibility is usually taken into account. The few approaches enabling docking with a flexible backbone typically work in two steps, in which the search for protein–protein orientations and [...] Read more.
Most of the protein–protein docking methods treat proteins as almost rigid objects. Only the side-chains flexibility is usually taken into account. The few approaches enabling docking with a flexible backbone typically work in two steps, in which the search for protein–protein orientations and structure flexibility are simulated separately. In this work, we propose a new straightforward approach for docking sampling. It consists of a single simulation step during which a protein undergoes large-scale backbone rearrangements, rotations, and translations. Simultaneously, the other protein exhibits small backbone fluctuations. Such extensive sampling was possible using the CABS coarse-grained protein model and Replica Exchange Monte Carlo dynamics at a reasonable computational cost. In our proof-of-concept simulations of 62 protein–protein complexes, we obtained acceptable quality models for a significant number of cases. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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17 pages, 1565 KiB  
Article
Association between Predicted Effects of TP53 Missense Variants on Protein Conformation and Their Phenotypic Presentation as Li-Fraumeni Syndrome or Hereditary Breast Cancer
by Yaxuan Liu, Olga Axell, Tom van Leeuwen, Robert Konrat, Pedram Kharaziha, Catharina Larsson, Anthony P. H. Wright and Svetlana Bajalica-Lagercrantz
Int. J. Mol. Sci. 2021, 22(12), 6345; https://doi.org/10.3390/ijms22126345 - 14 Jun 2021
Cited by 3 | Viewed by 2517
Abstract
Rare germline pathogenic TP53 missense variants often predispose to a wide spectrum of tumors characterized by Li-Fraumeni syndrome (LFS) but a subset of variants is also seen in families with exclusively hereditary breast cancer (HBC) outcomes. We have developed a logistic regression model [...] Read more.
Rare germline pathogenic TP53 missense variants often predispose to a wide spectrum of tumors characterized by Li-Fraumeni syndrome (LFS) but a subset of variants is also seen in families with exclusively hereditary breast cancer (HBC) outcomes. We have developed a logistic regression model with the aim of predicting LFS and HBC outcomes, based on the predicted effects of individual TP53 variants on aspects of protein conformation. A total of 48 missense variants either unique for LFS (n = 24) or exclusively reported in HBC (n = 24) were included. LFS-variants were over-represented in residues tending to be buried in the core of the tertiary structure of TP53 (p = 0.0014). The favored logistic regression model describes disease outcome in terms of explanatory variables related to the surface or buried status of residues as well as their propensity to contribute to protein compactness or protein-protein interactions. Reduced, internally validated models discriminated well between LFS and HBC (C-statistic = 0.78−0.84; equivalent to the area under the ROC (receiver operating characteristic) curve), had a low risk for over-fitting and were well calibrated in relation to the known outcome risk. In conclusion, this study presents a phenotypic prediction model of LFS and HBC risk for germline TP53 missense variants, in an attempt to provide a complementary tool for future decision making and clinical handling. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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18 pages, 3527 KiB  
Article
Pressure and Chemical Unfolding of an α-Helical Bundle Protein: The GH2 Domain of the Protein Adaptor GIPC1
by Cécile Dubois, Vicente J. Planelles-Herrero, Camille Tillatte-Tripodi, Stéphane Delbecq, Léa Mammri, Elena M. Sirkia, Virginie Ropars, Christian Roumestand and Philippe Barthe
Int. J. Mol. Sci. 2021, 22(7), 3597; https://doi.org/10.3390/ijms22073597 - 30 Mar 2021
Cited by 3 | Viewed by 1857
Abstract
When combined with NMR spectroscopy, high hydrostatic pressure is an alternative perturbation method used to destabilize globular proteins that has proven to be particularly well suited for exploring the unfolding energy landscape of small single-domain proteins. To date, investigations of the unfolding landscape [...] Read more.
When combined with NMR spectroscopy, high hydrostatic pressure is an alternative perturbation method used to destabilize globular proteins that has proven to be particularly well suited for exploring the unfolding energy landscape of small single-domain proteins. To date, investigations of the unfolding landscape of all-β or mixed-α/β protein scaffolds are well documented, whereas such data are lacking for all-α protein domains. Here we report the NMR study of the unfolding pathways of GIPC1-GH2, a small α-helical bundle domain made of four antiparallel α-helices. High-pressure perturbation was combined with NMR spectroscopy to unravel the unfolding landscape at three different temperatures. The results were compared to those obtained from classical chemical denaturation. Whatever the perturbation used, the loss of secondary and tertiary contacts within the protein scaffold is almost simultaneous. The unfolding transition appeared very cooperative when using high pressure at high temperature, as was the case for chemical denaturation, whereas it was found more progressive at low temperature, suggesting the existence of a complex folding pathway. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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16 pages, 21094 KiB  
Article
Configurational Entropy of Folded Proteins and Its Importance for Intrinsically Disordered Proteins
by Meili Liu, Akshaya K. Das, James Lincoff, Sukanya Sasmal, Sara Y. Cheng, Robert M. Vernon, Julie D. Forman-Kay and Teresa Head-Gordon
Int. J. Mol. Sci. 2021, 22(7), 3420; https://doi.org/10.3390/ijms22073420 - 26 Mar 2021
Cited by 10 | Viewed by 3087
Abstract
Many pairwise additive force fields are in active use for intrinsically disordered proteins (IDPs) and regions (IDRs), some of which modify energetic terms to improve the description of IDPs/IDRs but are largely in disagreement with solution experiments for the disordered states. This work [...] Read more.
Many pairwise additive force fields are in active use for intrinsically disordered proteins (IDPs) and regions (IDRs), some of which modify energetic terms to improve the description of IDPs/IDRs but are largely in disagreement with solution experiments for the disordered states. This work considers a new direction—the connection to configurational entropy—and how it might change the nature of our understanding of protein force field development to equally well encompass globular proteins, IDRs/IDPs, and disorder-to-order transitions. We have evaluated representative pairwise and many-body protein and water force fields against experimental data on representative IDPs and IDRs, a peptide that undergoes a disorder-to-order transition, for seven globular proteins ranging in size from 130 to 266 amino acids. We find that force fields with the largest statistical fluctuations consistent with the radius of gyration and universal Lindemann values for folded states simultaneously better describe IDPs and IDRs and disorder-to-order transitions. Hence, the crux of what a force field should exhibit to well describe IDRs/IDPs is not just the balance between protein and water energetics but the balance between energetic effects and configurational entropy of folded states of globular proteins. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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Review

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18 pages, 855 KiB  
Review
Is Protein Folding a Thermodynamically Unfavorable, Active, Energy-Dependent Process?
by Irina Sorokina, Arcady R. Mushegian and Eugene V. Koonin
Int. J. Mol. Sci. 2022, 23(1), 521; https://doi.org/10.3390/ijms23010521 - 4 Jan 2022
Cited by 22 | Viewed by 6665
Abstract
The prevailing current view of protein folding is the thermodynamic hypothesis, under which the native folded conformation of a protein corresponds to the global minimum of Gibbs free energy G. We question this concept and show that the empirical evidence behind the [...] Read more.
The prevailing current view of protein folding is the thermodynamic hypothesis, under which the native folded conformation of a protein corresponds to the global minimum of Gibbs free energy G. We question this concept and show that the empirical evidence behind the thermodynamic hypothesis of folding is far from strong. Furthermore, physical theory-based approaches to the prediction of protein folds and their folding pathways so far have invariably failed except for some very small proteins, despite decades of intensive theory development and the enormous increase of computer power. The recent spectacular successes in protein structure prediction owe to evolutionary modeling of amino acid sequence substitutions enhanced by deep learning methods, but even these breakthroughs provide no information on the protein folding mechanisms and pathways. We discuss an alternative view of protein folding, under which the native state of most proteins does not occupy the global free energy minimum, but rather, a local minimum on a fluctuating free energy landscape. We further argue that ΔG of folding is likely to be positive for the majority of proteins, which therefore fold into their native conformations only through interactions with the energy-dependent molecular machinery of living cells, in particular, the translation system and chaperones. Accordingly, protein folding should be modeled as it occurs in vivo, that is, as a non-equilibrium, active, energy-dependent process. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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1 pages, 156 KiB  
Correction
Correction: Cserző et al. The First Quarter Century of the Dense Alignment Surface Transmembrane Prediction Method. Int. J. Mol. Sci. 2023, 24, 14016
by Miklós Cserző, Birgit Eisenhaber, Frank Eisenhaber, Csaba Magyar and István Simon
Int. J. Mol. Sci. 2024, 25(6), 3422; https://doi.org/10.3390/ijms25063422 - 18 Mar 2024
Viewed by 465
Abstract
There was an error in the original publication [...] Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
6 pages, 1846 KiB  
Commentary
Oxidative Folding of Proteins: The “Smoking Gun” of Glutathione
by Alessio Bocedi, Giada Cattani, Giorgia Gambardella, Linda Schulte, Harald Schwalbe and Giorgio Ricci
Int. J. Mol. Sci. 2021, 22(18), 10148; https://doi.org/10.3390/ijms221810148 - 20 Sep 2021
Cited by 4 | Viewed by 1937
Abstract
Glutathione has long been suspected to be the primary low molecular weight compound present in all cells promoting the oxidative protein folding, but twenty years ago it was found “not guilty”. Now, new surprising evidence repeats its request to be the “smoking gun” [...] Read more.
Glutathione has long been suspected to be the primary low molecular weight compound present in all cells promoting the oxidative protein folding, but twenty years ago it was found “not guilty”. Now, new surprising evidence repeats its request to be the “smoking gun” which reopens the criminal trial revealing the crucial involvement of this tripeptide. Full article
(This article belongs to the Special Issue Frontiers in Protein Structure Research)
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