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Special Issue "Protein Folding 2011"

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

Deadline for manuscript submissions: closed (30 April 2011)

Special Issue Editor

Guest Editor
Prof. Dr. Charles Gerday

Laboratory of Biochemistry, University of Liège, Institute of Chemistry, B6a, B-4000, Liège, Belgium
E-Mail
Interests: protein chemistry; enzymology; microbiology; molecular adaptations to low temperature; extremophiles

Special Issue Information

Dear Colleagues,

The folding of proteins is recognized as one of the most complex processes in Biochemistry since its understanding also implies the characterization, from the unfolded state, of all conformational changes such as intermediate and transition states that separate the unfolded polypeptide from its fully folded and active form. The situation is also rendered more complicated because most of the proteins are made of several domains all having their own thermodynamic and kinetics parameters of folding. Counter pressures are also exerted by the possible existence of disulfide bridges which have to be appropriately paired through oxidative processes driven by the Dsb disulfide bonds generation machinery implicating oxido-reductases and isomerases as well as by the existence of the cis- and trans- possible configuration of the peptide bonds immediately preceding the prolyl residues. This cis-trans isomerization is dependent on an ubiquitous class of foldases known as peptidyl-prolyl cis-trans isomerases. The folding of nascent polypeptides is also assisted by special proteins, known as chaperones that also play crucial roles in protecting proteins against irreversible misfolding possibly induced by various cellular stresses such as heat shock or cold shock for example. Although the existence of intermediates are not always required for efficient folding they are obviously generally essential in helping to restrict the conformational zones and to direct the molecule towards its final low energy state. They have been identified and monitored by stopped-flow techniques making use of chemical denaturants or physical methods such as pressure perturbation recently found to be quite able to precise the folding landscape of a protein that provides the basis of the understanding of protein folding.

The aim of this special issue is to illustrate, through selected examples, the progresses which has been recently made, both on theoretical and technical grounds, in the understanding of the folding process of proteins nowadays of crucial importance due to the discovery of the relationship existing between protein misfolding and various human diseases derived from neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease.

Prof. Dr. Charles Gerday
Guest Editor

Keywords

  • protein folding
  • chaperones
  • foldases
  • stopped-flow
  • energy landscape

Related Special Issues

Published Papers (6 papers)

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Research

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Open AccessArticle Intermediates in the Protein Folding Process: A Computational Model
Int. J. Mol. Sci. 2011, 12(8), 4850-4860; doi:10.3390/ijms11084850
Received: 7 April 2011 / Revised: 7 June 2011 / Accepted: 25 July 2011 / Published: 29 July 2011
Cited by 5 | PDF Full-text (648 KB) | HTML Full-text | XML Full-text
Abstract
The paper presents a model for simulating the protein folding process in silico. The two-step model (which consists of the early stage—ES and the late stage—LS) is verified using two proteins, one of which is treated (according to experimental observations) as the
[...] Read more.
The paper presents a model for simulating the protein folding process in silico. The two-step model (which consists of the early stage—ES and the late stage—LS) is verified using two proteins, one of which is treated (according to experimental observations) as the early stage and the second as an example of the LS step. The early stage is based solely on backbone structural preferences, while the LS model takes into account the water environment, treated as an external hydrophobic force field and represented by a 3D Gauss function. The characteristics of 1ZTR (the ES intermediate, as compared with 1ENH, which is the LS intermediate) confirm the link between the gradual disappearance of ES characteristics in LS structural forms and the simultaneous emergence of LS properties in the 1ENH protein. Positive verification of ES and LS characteristics in these two proteins (1ZTR and 1ENH respectively) suggest potential applicability of the presented model to in silico protein folding simulations. Full article
(This article belongs to the Special Issue Protein Folding 2011)
Open AccessArticle Acid-Denatured Green Fluorescent Protein (GFP) as Model Substrate to Study the Chaperone Activity of Protein Disulfide Isomerase
Int. J. Mol. Sci. 2011, 12(7), 4625-4636; doi:10.3390/ijms12074625
Received: 3 May 2011 / Revised: 17 June 2011 / Accepted: 4 July 2011 / Published: 18 July 2011
Cited by 7 | PDF Full-text (420 KB) | HTML Full-text | XML Full-text
Abstract
Green fluorescent protein (GFP) has been widely used in several molecular and cellular biology applications, since it is remarkably stable in vitro and in vivo. Interestingly, native GFP is resistant to the most common chemical denaturants; however, a low fluorescence signal has
[...] Read more.
Green fluorescent protein (GFP) has been widely used in several molecular and cellular biology applications, since it is remarkably stable in vitro and in vivo. Interestingly, native GFP is resistant to the most common chemical denaturants; however, a low fluorescence signal has been observed after acid-induced denaturation. Furthermore, this acid-denatured GFP has been used as substrate in studies of the folding activity of some bacterial chaperones and other chaperone-like molecules. Protein disulfide isomerase enzymes, a family of eukaryotic oxidoreductases that catalyze the oxidation and isomerization of disulfide bonds in nascent polypeptides, play a key role in protein folding and it could display chaperone activity. However, contrasting results have been reported using different proteins as model substrates. Here, we report the further application of GFP as a model substrate to study the chaperone activity of protein disulfide isomerase (PDI) enzymes. Since refolding of acid-denatured GFP can be easily and directly monitored, a simple micro-assay was used to study the effect of the molecular participants in protein refolding assisted by PDI. Additionally, the effect of a well-known inhibitor of PDI chaperone activity was also analyzed. Because of the diversity their functional activities, PDI enzymes are potentially interesting drug targets. Since PDI may be implicated in the protection of cells against ER stress, including cancer cells, inhibitors of PDI might be able to enhance the efficacy of cancer chemotherapy; furthermore, it has been demonstrated that blocking the reductive cleavage of disulfide bonds of proteins associated with the cell surface markedly reduces the infectivity of the human immunodeficiency virus. Although several high-throughput screening (HTS) assays to test PDI reductase activity have been described, we report here a novel and simple micro-assay to test the chaperone activity of PDI enzymes, which is amenable for HTS of PDI inhibitors. Full article
(This article belongs to the Special Issue Protein Folding 2011)
Figures

Open AccessArticle Impact of the 237th Residue on the Folding of Human Carbonic Anhydrase II
Int. J. Mol. Sci. 2011, 12(5), 2797-2807; doi:10.3390/ijms12052797
Received: 4 March 2011 / Revised: 7 April 2011 / Accepted: 12 April 2011 / Published: 28 April 2011
Cited by 3 | PDF Full-text (482 KB) | HTML Full-text | XML Full-text
Abstract
The deficiency of human carbonic anhydrase II (HCAII) has been recognized to be associated with a disease called CAII deficiency syndrome (CADS). Among the many mutations, the P237H mutation has been characterized to lead to a significant decrease in the activity of the
[...] Read more.
The deficiency of human carbonic anhydrase II (HCAII) has been recognized to be associated with a disease called CAII deficiency syndrome (CADS). Among the many mutations, the P237H mutation has been characterized to lead to a significant decrease in the activity of the enzyme and in the Gibbs free energy of folding. However, sequence alignment indicated that the 237th residue of CAII is not fully conserved across all species. The FoldX theoretical calculations suggested that this residue did not significantly contribute to the overall folding of HCAII, since all mutants had small ΔΔG values (around 1 kcal/mol). The experimental determination indicated that at least three mutations affect HCAII folding significantly and the P237H mutation was the most deleterious one, suggesting that Pro237 was important to HCAII folding. The discrepancy between theoretical and experimental results suggested that caution should be taken when using the prediction methods to evaluate the details of disease-related mutations. Full article
(This article belongs to the Special Issue Protein Folding 2011)
Open AccessArticle Characterization of a Deswapped Triple Mutant Bovine Odorant Binding Protein
Int. J. Mol. Sci. 2011, 12(4), 2294-2314; doi:10.3390/ijms12042294
Received: 1 March 2011 / Revised: 16 March 2011 / Accepted: 29 March 2011 / Published: 4 April 2011
Cited by 1 | PDF Full-text (725 KB) | HTML Full-text | XML Full-text
Abstract
The stability and functionality of GCC-bOBP, a monomeric triple mutant of bovine odorant binding protein, was investigated, in the presence of denaturant and in acidic pH conditions, by both protein and 1-aminoanthracene ligand fluorescence measurements, and compared to that of both bovine and
[...] Read more.
The stability and functionality of GCC-bOBP, a monomeric triple mutant of bovine odorant binding protein, was investigated, in the presence of denaturant and in acidic pH conditions, by both protein and 1-aminoanthracene ligand fluorescence measurements, and compared to that of both bovine and porcine wild type homologues. Complete reversibility of unfolding was observed, though refolding was characterized by hysteresis. Molecular dynamics simulations, performed to detect possible structural changes of the monomeric scaffold related to the presence of the ligand, pointed out the stability of the β-barrel lipocalin scaffold. Full article
(This article belongs to the Special Issue Protein Folding 2011)
Figures

Open AccessArticle Stability and Folding Behavior Analysis of Zinc-Finger Using Simple Models
Int. J. Mol. Sci. 2010, 11(10), 4014-4034; doi:10.3390/ijms11104014
Received: 7 September 2010 / Revised: 1 October 2010 / Accepted: 9 October 2010 / Published: 19 October 2010
Cited by 12 | PDF Full-text (805 KB) | HTML Full-text | XML Full-text
Abstract
Zinc-fingers play crucial roles in regulating gene expression and mediating protein-protein interactions. In this article, two different proteins (Sp1f2 and FSD-1) are investigated using the Gaussian network model and anisotropy elastic network model. By using these simple coarse-grained methods, we analyze the structural
[...] Read more.
Zinc-fingers play crucial roles in regulating gene expression and mediating protein-protein interactions. In this article, two different proteins (Sp1f2 and FSD-1) are investigated using the Gaussian network model and anisotropy elastic network model. By using these simple coarse-grained methods, we analyze the structural stabilization and establish the unfolding pathway of the two different proteins, in good agreement with related experimental and molecular dynamics simulation data. From the analysis, it is also found that the folding process of the zinc-finger motif is predominated by several factors. Both the zinc ion and C-terminal loop affect the folding pathway of the zinc-finger motif. Knowledge about the stability and folding behavior of zinc-fingers may help in understanding the folding mechanisms of the zinc-finger motif and in designing new zinc-fingers. Meanwhile, these simple coarse-grained analyses can be used as a general and quick method for mechanistic studies of metalloproteins. Full article
(This article belongs to the Special Issue Protein Folding 2011)
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Review

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Open AccessReview FK506-Binding Protein 22 from a Psychrophilic Bacterium, a Cold Shock-Inducible Peptidyl Prolyl Isomerase with the Ability to Assist in Protein Folding
Int. J. Mol. Sci. 2011, 12(8), 5261-5284; doi:10.3390/ijms12085261
Received: 12 May 2011 / Revised: 28 July 2011 / Accepted: 9 August 2011 / Published: 17 August 2011
Cited by 11 | PDF Full-text (834 KB) | HTML Full-text | XML Full-text
Abstract
Adaptation of microorganisms to low temperatures remains to be fully elucidated. It has been previously reported that peptidyl prolyl cis-trans isomerases (PPIases) are involved in cold adaptation of various microorganisms whether they are hyperthermophiles, mesophiles or phsycrophiles. The rate of cis-trans isomerization at
[...] Read more.
Adaptation of microorganisms to low temperatures remains to be fully elucidated. It has been previously reported that peptidyl prolyl cis-trans isomerases (PPIases) are involved in cold adaptation of various microorganisms whether they are hyperthermophiles, mesophiles or phsycrophiles. The rate of cis-trans isomerization at low temperatures is much slower than that at higher temperatures and may cause problems in protein folding. However, the mechanisms by which PPIases are involved in cold adaptation remain unclear. Here we used FK506-binding protein 22, a cold shock protein from the psychrophilic bacterium Shewanella sp. SIB1 (SIB1 FKBP22) as a model protein to decipher the involvement of PPIases in cold adaptation. SIB1 FKBP22 is homodimer that assumes a V-shaped structure based on a tertiary model. Each monomer consists of an N-domain responsible for dimerization and a C-catalytic domain. SIB1 FKBP22 is a typical cold-adapted enzyme as indicated by the increase of catalytic efficiency at low temperatures, the downward shift in optimal temperature of activity and the reduction in the conformational stability. SIB1 FKBP22 is considered as foldase and chaperone based on its ability to catalyze refolding of a cis-proline containing protein and bind to a folding intermediate protein, respectively. The foldase and chaperone activites of SIB1 FKBP22 are thought to be important for cold adaptation of Shewanella sp. SIB1. These activities are also employed by other PPIases for being involved in cold adaptation of various microorganisms. Despite other biological roles of PPIases, we proposed that foldase and chaperone activities of PPIases are the main requirement for overcoming the cold-stress problem in microorganisms due to folding of proteins. Full article
(This article belongs to the Special Issue Protein Folding 2011)

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