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Protein Folding 2.0

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

Deadline for manuscript submissions: 20 June 2024 | Viewed by 3881

Special Issue Editor


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Guest Editor
1. Institute of Biotechnology and Biomedicine, Autonomous University of Barcelona, 08193 Bellaterra, Spain
2. Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08193 Bellaterra, Spain
Interests: protein folding; protein aggregation; protein design; high-throughput screening; bioinformatics; amyloids; Parkinson; nanomaterials; phase separation; prions; drug discovery
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous successful Special Issue “Protein Folding”.

Protein folding is among the most complex and challenging processes in biochemistry. After synthesis at the ribosome, most polypeptides must fold into their specific three-dimensional structures before they can exert any biological function. Only properly folded conformers can interact specifically with their molecular targets. Therefore, protein folding is central to many biological processes. It has long been known that the functional structure of a protein is coded by its primary one-dimensional amino acid sequence. Although the molecular mechanisms behind the folding code are not yet completely understood, we have witnessed significant advances towards this goal in recent years, resulting not only from the development of new experimental approaches and sophisticated prediction methods, but also arising from new ways of thinking about protein folding and dynamics. Folding within biomembranes, multi-domain protein folding, folding in the cell, molecular chaperone-assisted folding and the dynamics of intrinsically disordered proteins are among the newest and most active areas of research. Although protein folding and dynamics are behind virtually all cell reactions, ranging from transcription to motion, it is the link to human disease that has placed this subject in the public eye. Protein misfolding and subsequent aggregation have been shown to underlie dozens of human disorders. In order to elucidate the ways that misfolded proteins cause aggregation and cytotoxicity, it is necessary to better understand and predict protein folding. Thus, in a scientific environment that promotes technology transfer, it is encouraging to learn that the first principles approach holds the clue for therapeutic interventions in devastating disorders such as Parkinson’s and Alzheimer’s disease. The aim of this Special Issue is to illustrate frontier research in protein folding through selected works on this topic.

Prof. Dr. Salvador Ventura
Guest Editor

Manuscript Submission Information

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Keywords

  • amyloid
  • calorimetry
  • chaperones
  • crowding and folding
  • downhill folding
  • energy lanscape
  • folding in biomembranes
  • folding in the cell
  • folding intermediates
  • folding kinetics
  • intrinsically disordered proteins
  • molecular dynamics simulation of folding
  • oxidative folding
  • protein aggregation
  • protein folding and design
  • protein folding and docking
  • protein folding and evolution
  • protein misfolding
  • single molecule folding
  • transition state analysis

Related Special Issue

Published Papers (3 papers)

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Research

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14 pages, 4301 KiB  
Article
Vitamin K Epoxide Reductase Complex–Protein Disulphide Isomerase Assemblies in the Thiol–Disulphide Exchange Reactions: Portrayal of Precursor-to-Successor Complexes
by Maxim Stolyarchuk, Marina Botnari and Luba Tchertanov
Int. J. Mol. Sci. 2024, 25(8), 4135; https://doi.org/10.3390/ijms25084135 - 9 Apr 2024
Viewed by 681
Abstract
The human Vitamin K Epoxide Reductase Complex (hVKORC1), a key enzyme that converts vitamin K into the form necessary for blood clotting, requires for its activation the reducing equivalents supplied by its redox partner through thiol–disulphide exchange reactions. The functionally related molecular complexes [...] Read more.
The human Vitamin K Epoxide Reductase Complex (hVKORC1), a key enzyme that converts vitamin K into the form necessary for blood clotting, requires for its activation the reducing equivalents supplied by its redox partner through thiol–disulphide exchange reactions. The functionally related molecular complexes assembled during this process have never been described, except for a proposed de novo model of a ‘precursor’ complex of hVKORC1 associated with protein disulphide isomerase (PDI). Using numerical approaches (in silico modelling and molecular dynamics simulation), we generated alternative 3D models for each molecular complex bonded either covalently or non-covalently. These models differ in the orientation of the PDI relative to hVKORC1 and in the cysteine residue involved in forming protein–protein disulphide bonds. Based on a comparative analysis of these models’ shape, folding, and conformational dynamics, the most probable putative complexes, mimicking the ‘precursor’, ‘intermediate’, and ‘successor’ states, were suggested. In addition, we propose using these complexes to develop the ‘allo-network drugs’ necessary for treating blood diseases. Full article
(This article belongs to the Special Issue Protein Folding 2.0)
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20 pages, 1934 KiB  
Article
Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1
by Madalena Barroso, Marcus Gertzen, Alexandra F. Puchwein-Schwepcke, Heike Preisler, Andreas Sturm, Dunja D. Reiss, Marta K. Danecka, Ania C. Muntau and Søren W. Gersting
Int. J. Mol. Sci. 2023, 24(17), 13158; https://doi.org/10.3390/ijms241713158 - 24 Aug 2023
Cited by 1 | Viewed by 1656
Abstract
Glutaric acidemia type 1 (GA1) is a neurotoxic metabolic disorder due to glutaryl-CoA dehydrogenase (GCDH) deficiency. The high number of missense variants associated with the disease and their impact on GCDH activity suggest that disturbed protein conformation can affect the biochemical phenotype. We [...] Read more.
Glutaric acidemia type 1 (GA1) is a neurotoxic metabolic disorder due to glutaryl-CoA dehydrogenase (GCDH) deficiency. The high number of missense variants associated with the disease and their impact on GCDH activity suggest that disturbed protein conformation can affect the biochemical phenotype. We aimed to elucidate the molecular basis of protein loss of function in GA1 by performing a parallel analysis in a large panel of GCDH missense variants using different biochemical and biophysical methodologies. Thirteen GCDH variants were investigated in regard to protein stability, hydrophobicity, oligomerization, aggregation, and activity. An altered oligomerization, loss of protein stability and solubility, as well as an augmented susceptibility to aggregation were observed. GA1 variants led to a loss of enzymatic activity, particularly when present at the N-terminal domain. The reduced cellular activity was associated with loss of tetramerization. Our results also suggest a correlation between variant sequence location and cellular protein stability (p < 0.05), with a more pronounced loss of protein observed with variant proximity to the N-terminus. The broad panel of variant-mediated conformational changes of the GCDH protein supports the classification of GA1 as a protein-misfolding disorder. This work supports research toward new therapeutic strategies that target this molecular disease phenotype. Full article
(This article belongs to the Special Issue Protein Folding 2.0)
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Review

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16 pages, 7456 KiB  
Review
Membrane-Driven Dimerization of the Peripheral Membrane Protein KRAS: Implications for Downstream Signaling
by Ki-Young Lee
Int. J. Mol. Sci. 2024, 25(5), 2530; https://doi.org/10.3390/ijms25052530 - 21 Feb 2024
Viewed by 1080
Abstract
Transient homo-dimerization of the RAS GTPase at the plasma membrane has been shown to promote the mitogen-activated protein kinase (MAPK) signaling pathway essential for cell proliferation and oncogenesis. To date, numerous crystallographic studies have focused on the well-defined GTPase domains of RAS isoforms, [...] Read more.
Transient homo-dimerization of the RAS GTPase at the plasma membrane has been shown to promote the mitogen-activated protein kinase (MAPK) signaling pathway essential for cell proliferation and oncogenesis. To date, numerous crystallographic studies have focused on the well-defined GTPase domains of RAS isoforms, which lack the disordered C-terminal membrane anchor, thus providing limited structural insight into membrane-bound RAS molecules. Recently, lipid-bilayer nanodisc platforms and paramagnetic relaxation enhancement (PRE) analyses have revealed several distinct structures of the membrane-anchored homodimers of KRAS, an isoform that is most frequently mutated in human cancers. The KRAS dimerization interface is highly plastic and altered by biologically relevant conditions, including oncogenic mutations, the nucleotide states of the protein, and the lipid composition. Notably, PRE-derived structures of KRAS homodimers on the membrane substantially differ in terms of the relative orientation of the protomers at an “α–α” dimer interface comprising two α4–α5 regions. This interface plasticity along with the altered orientations of KRAS on the membrane impact the accessibility of KRAS to downstream effectors and regulatory proteins. Further, nanodisc platforms used to drive KRAS dimerization can be used to screen potential anticancer drugs that target membrane-bound RAS dimers and probe their structural mechanism of action. Full article
(This article belongs to the Special Issue Protein Folding 2.0)
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