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Protein Structure Research 2024

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: 30 June 2024 | Viewed by 5903

Special Issue Editors


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Guest Editor
Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, 1117 Budapest, Hungary
Interests: protein bioinformatics; protein interactions; membrane proteins; protein stability; intrinsically disordered proteins; protein structure; protein folding; protein biophysics; protein binding; protein dynamics; protein conformation; molecular biophysics; protein refolding; membrane transport proteins; computational structural biology; structural bioinformatics
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
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 have opened up in protein structure research. Besides the traditional forms of proteins, such as folded water-soluble proteins, transmembrane- and membrane-associated proteins, and disordered proteins which are able to fold on the surface of folded proteins or other stable mac romolecules, new forms of proteins and protein complexes have emerged. Among others, fuzzy complexes in which, during physiological function, at least one protein component is still in disordered form; and mutual synergistic folding complexes, in which two or more disordered proteins help each other to fold, are new subclasses of proteins. Combinations of the above-mentioned proteins, such as partially disordered proteins or proteins participating in liquid–liquid phase separation, represent new forms of proteins. These all encompass new and interesting fields of protein structure research.

As the guest editors of this Special Issue of IJMS titled “Protein Structure Research 2024”, 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

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

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

Published Papers (4 papers)

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Research

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16 pages, 3619 KiB  
Article
Channel Formation in Cry Toxins: An Alphafold-2 Perspective
by Jaume Torres, Wahyu Surya and Panadda Boonserm
Int. J. Mol. Sci. 2023, 24(23), 16809; https://doi.org/10.3390/ijms242316809 - 27 Nov 2023
Cited by 1 | Viewed by 992
Abstract
Bacillus thuringiensis (Bt) strains produce pore-forming toxins (PFTs) that attack insect pests. Information for pre-pore and pore structures of some of these Bt toxins is available. However, for the three-domain (I-III) crystal (Cry) toxins, the most used Bt toxins in pest control, this [...] Read more.
Bacillus thuringiensis (Bt) strains produce pore-forming toxins (PFTs) that attack insect pests. Information for pre-pore and pore structures of some of these Bt toxins is available. However, for the three-domain (I-III) crystal (Cry) toxins, the most used Bt toxins in pest control, this crucial information is still missing. In these Cry toxins, biochemical data have shown that 7-helix domain I is involved in insertion in membranes, oligomerization and formation of a channel lined mainly by helix α4, whereas helices α1 to α3 seem to have a dynamic role during insertion. In the case of Cry1Aa, toxic against Manduca sexta larvae, a tetrameric oligomer seems to precede membrane insertion. Given the experimental difficulty in the elucidation of the membrane insertion steps, we used Alphafold-2 (AF2) to shed light on possible oligomeric structural intermediates in the membrane insertion of this toxin. AF2 very accurately (<1 Å RMSD) predicted the crystal monomeric and trimeric structures of Cry1Aa and Cry4Ba. The prediction of a tetramer of Cry1Aa, but not Cry4Ba, produced an ‘extended model’ where domain I helices α3 and α2b form a continuous helix and where hydrophobic helices α1 and α2 cluster at the tip of the bundle. We hypothesize that this represents an intermediate that binds the membrane and precedes α4/α5 hairpin insertion, together with helices α6 and α7. Another Cry1Aa tetrameric model was predicted after deleting helices α1 to α3, where domain I produced a central cavity consistent with an ion channel, lined by polar and charged residues in helix α4. We propose that this second model corresponds to the ‘membrane-inserted’ structure. AF2 also predicted larger α4/α5 hairpin n-mers (14 ≤n ≤ 17) with high confidence, which formed even larger (~5 nm) pores. The plausibility of these models is discussed in the context of available experimental data and current paradigms. Full article
(This article belongs to the Special Issue Protein Structure Research 2024)
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20 pages, 3694 KiB  
Article
The Intrinsically Disordered N Terminus in Atg12 from Yeast Is Necessary for the Functional Structure of the Protein
by Hana Popelka, Vikramjit Lahiri, Wayne D. Hawkins, Felipe da Veiga Leprevost, Alexey I. Nesvizhskii and Daniel J. Klionsky
Int. J. Mol. Sci. 2023, 24(20), 15036; https://doi.org/10.3390/ijms242015036 - 10 Oct 2023
Cited by 1 | Viewed by 1162
Abstract
The Atg12 protein in yeast is an indispensable polypeptide in the highly conserved ubiquitin-like conjugation system operating in the macroautophagy/autophagy pathway. Atg12 is covalently conjugated to Atg5 through the action of Atg7 and Atg10; the Atg12–Atg5 conjugate binds Atg16 to form an E3 [...] Read more.
The Atg12 protein in yeast is an indispensable polypeptide in the highly conserved ubiquitin-like conjugation system operating in the macroautophagy/autophagy pathway. Atg12 is covalently conjugated to Atg5 through the action of Atg7 and Atg10; the Atg12–Atg5 conjugate binds Atg16 to form an E3 ligase that functions in a separate conjugation pathway involving Atg8. Atg12 is comprised of a ubiquitin-like (UBL) domain preceded at the N terminus by an intrinsically disordered protein region (IDPR), a domain that comprises a major portion of the protein but remains elusive in its conformation and function. Here, we show that the IDPR in unconjugated Atg12 is positioned in proximity to the UBL domain, a configuration that is important for the functional structure of the protein. A major deletion in the IDPR disrupts intactness of the UBL domain at the unconjugated C terminus, and a mutation in the predicted α0 helix in the IDPR prevents Atg12 from binding to Atg7 and Atg10, which ultimately affects the protein function in the ubiquitin-like conjugation cascade. These findings provide evidence that the IDPR is an indispensable part of the Atg12 protein from yeast. Full article
(This article belongs to the Special Issue Protein Structure Research 2024)
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Review

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17 pages, 1710 KiB  
Review
Could Targeting NPM1c+ Misfolding Be a Promising Strategy for Combating Acute Myeloid Leukemia?
by Daniele Florio and Daniela Marasco
Int. J. Mol. Sci. 2024, 25(2), 811; https://doi.org/10.3390/ijms25020811 - 9 Jan 2024
Viewed by 1181
Abstract
Acute myeloid leukemia (AML) is a heterogeneous group of diseases classified into various types on the basis of distinct features concerning the morphology, cytochemistry and cytogenesis of leukemic cells. Among the different subtypes, the group “AML with gene mutations” includes the variations of [...] Read more.
Acute myeloid leukemia (AML) is a heterogeneous group of diseases classified into various types on the basis of distinct features concerning the morphology, cytochemistry and cytogenesis of leukemic cells. Among the different subtypes, the group “AML with gene mutations” includes the variations of the gene of the multifunctional protein nucleophosmin 1 (NPM1). These mutations are the most frequent (~30–35% of AML adult patients and less in pediatric ones) and occur predominantly in the C-terminal domain (CTD) of NPM1. The most important mutation is the insertion at W288, which determines the frame shift W288Cfs12/Ffs12/Lfs*12 and leads to the addition of 2–12 amino acids, which hamper the correct folding of NPM1. This mutation leads to the loss of the nuclear localization signal (NoLS) and to aberrant cytoplasmic localization, denoted as NPM1c+. Many investigations demonstrated that interfering with the cellular location and oligomerization status of NPM1 can influence its biological functions, including the proper buildup of the nucleolus, and therapeutic strategies have been proposed to target NPM1c+, particularly the use of drugs able to re-direct NPM1 localization. Our studies unveiled a direct link between AML mutations and the neat amyloidogenic character of the CTDs of NPM1c+. Herein, with the aim of exploiting these conformational features, novel therapeutic strategies are proposed that rely on the induction of the selective self-cytotoxicity of leukemic blasts by focusing on agents such as peptides, peptoids or small molecules able to enhance amyloid aggregation and targeting selectively AML–NPM1c+ mutations. Full article
(This article belongs to the Special Issue Protein Structure Research 2024)
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25 pages, 5971 KiB  
Review
Analyzing Current Trends and Possible Strategies to Improve Sucrose Isomerases’ Thermostability
by Amado Javier Sardiña-Peña, Liber Mesa-Ramos, Blanca Flor Iglesias-Figueroa, Lourdes Ballinas-Casarrubias, Tania Samanta Siqueiros-Cendón, Edward Alexander Espinoza-Sánchez, Norma Rosario Flores-Holguín, Sigifredo Arévalo-Gallegos and Quintín Rascón-Cruz
Int. J. Mol. Sci. 2023, 24(19), 14513; https://doi.org/10.3390/ijms241914513 - 25 Sep 2023
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Abstract
Due to their ability to produce isomaltulose, sucrose isomerases are enzymes that have caught the attention of researchers and entrepreneurs since the 1950s. However, their low activity and stability at temperatures above 40 °C have been a bottleneck for their industrial application. Specifically, [...] Read more.
Due to their ability to produce isomaltulose, sucrose isomerases are enzymes that have caught the attention of researchers and entrepreneurs since the 1950s. However, their low activity and stability at temperatures above 40 °C have been a bottleneck for their industrial application. Specifically, the instability of these enzymes has been a challenge when it comes to their use for the synthesis and manufacturing of chemicals on a practical scale. This is because industrial processes often require biocatalysts that can withstand harsh reaction conditions, like high temperatures. Since the 1980s, there have been significant advancements in the thermal stabilization engineering of enzymes. Based on the literature from the past few decades and the latest achievements in protein engineering, this article systematically describes the strategies used to enhance the thermal stability of sucrose isomerases. Additionally, from a theoretical perspective, we discuss other potential mechanisms that could be used for this purpose. Full article
(This article belongs to the Special Issue Protein Structure Research 2024)
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