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Biomolecules
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Protein Folding and Misfolding
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Protein Folding and Misfolding

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (27 December 2013) | Viewed by 199632

Special Issue Editor

Prof. Dr. Alexei V. Finkelstein

E-Mail Website
Guest Editor
Laboratory of Protein Physics, Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia
Interests: protein physics; protein structure; protein folding; protein folding intermediates; protein design; phase transitions; phase transition kinetics; transition states; antifreeze proteins; amyloids; protein bioinformatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The ability of protein chains to spontaneously form their spatial structures was a long-standing puzzle in molecular biology, especially because the measured rates of spontaneous folding range from microseconds to hours: the difference (at least 11 orders of magnitude) is akin to the difference between the life span of a mosquito and the age of the universe. Now, when this puzzle is solved in its basics, the main interest has been shifted (1) to the "natively disordered" proteins, which usually obtain their definite structure only when interact with target molecules, and (2) to the ability of many protein chains to form not only the "native" (properly working) 3D structures, but also the other ("misfolded") structures, which is also often connected with interaction of these chains with the other molecules.

These reconstructions of protein structures sometimes cause deadly diseases, and therefore the problem of protein folding and misfolding attains a great medical interest. Many new challenges are waiting in the field.

To illustrate for the readers of “Biomolecules” the importance of the protein folding and misfolding problem as a multidisciplinary field of research, this special issue is intended to show the various aspects of protein folding, misfolding and unfolding.

We look forward to reading your contributions.

Prof. Dr. Alexei V. Finkelstein
Guest Editor

Manuscript Submission Information

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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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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 folding
  • protein misfolding
  • protein unfolding
  • protein structure
  • natively disordered proteins
  • protein structure reconstruction
  • protein physics
  • protein engineering

Published Papers (21 papers)

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Research

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8089 KiB  
Article
Amino Acid Distribution Rules Predict Protein Fold: Protein Grammar for Beta-Strand Sandwich-Like Structures
by Alexander Kister
Biomolecules 2015, 5(1), 41-59; https://doi.org/10.3390/biom5010041 - 23 Jan 2015
Cited by 6 | Viewed by 7368
Abstract
We present an alternative approach to protein 3D folding prediction based on determination of rules that specify distribution of “favorable” residues, that are mainly responsible for a given fold formation, and “unfavorable” residues, that are incompatible with that fold, in polypeptide sequences. The [...] Read more.
We present an alternative approach to protein 3D folding prediction based on determination of rules that specify distribution of “favorable” residues, that are mainly responsible for a given fold formation, and “unfavorable” residues, that are incompatible with that fold, in polypeptide sequences. The process of determining favorable and unfavorable residues is iterative. The starting assumptions are based on the general principles of protein structure formation as well as structural features peculiar to a protein fold under investigation. The initial assumptions are tested one-by-one for a set of all known proteins with a given structure. The assumption is accepted as a “rule of amino acid distribution” for the protein fold if it holds true for all, or near all, structures. If the assumption is not accepted as a rule, it can be modified to better fit the data and then tested again in the next step of the iterative search algorithm, or rejected. We determined the set of amino acid distribution rules for a large group of beta sandwich-like proteins characterized by a specific arrangement of strands in two beta sheets. It was shown that this set of rules is highly sensitive (~90%) and very specific (~99%) for identifying sequences of proteins with specified beta sandwich fold structure. The advantage of the proposed approach is that it does not require that query proteins have a high degree of homology to proteins with known structure. So long as the query protein satisfies residue distribution rules, it can be confidently assigned to its respective protein fold. Another advantage of our approach is that it allows for a better understanding of which residues play an essential role in protein fold formation. It may, therefore, facilitate rational protein engineering design. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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67855 KiB  
Article
Probing the Kinetic Stabilities of Friedreich’s Ataxia Clinical Variants Using a Solid Phase GroEL Chaperonin Capture Platform
by Ana R. Correia, Subhashchandra Naik, Mark T. Fisher and Cláudio M. Gomes
Biomolecules 2014, 4(4), 956-979; https://doi.org/10.3390/biom4040956 - 20 Oct 2014
Cited by 4 | Viewed by 6289
Abstract
Numerous human diseases are caused by protein folding defects where the protein may become more susceptible to degradation or aggregation. Aberrant protein folding can affect the kinetic stability of the proteins even if these proteins appear to be soluble in vivo. Experimental [...] Read more.
Numerous human diseases are caused by protein folding defects where the protein may become more susceptible to degradation or aggregation. Aberrant protein folding can affect the kinetic stability of the proteins even if these proteins appear to be soluble in vivo. Experimental discrimination between functional properly folded and misfolded nonfunctional conformers is not always straightforward at near physiological conditions. The differences in the kinetic behavior of two initially folded frataxin clinical variants were examined using a high affinity chaperonin kinetic trap approach at 25 °C. The kinetically stable wild type frataxin (FXN) shows no visible partitioning onto the chaperonin. In contrast, the clinical variants FXN-p.Asp122Tyr and FXN-p.Ile154Phe kinetically populate partial folded forms that tightly bind the GroEL chaperonin platform. The initially soluble FXN-p.Ile154Phe variant partitions onto GroEL more rapidly and is more kinetically liable. These differences in kinetic stability were confirmed using differential scanning fluorimetry. The kinetic and aggregation stability differences of these variants may lead to the distinct functional impairments described in Friedreich’s ataxia, the neurodegenerative disease associated to frataxin functional deficiency. This chaperonin platform approach may be useful for identifying small molecule stabilizers since stabilizing ligands to frataxin variants should lead to a concomitant decrease in chaperonin binding. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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2071 KiB  
Article
Chaperonin GroEL Reassembly: An Effect of Protein Ligands and Solvent Composition
by Nataliya Ryabova, Victor Marchenkov, Nina Kotova and Gennady Semisotnov
Biomolecules 2014, 4(2), 458-473; https://doi.org/10.3390/biom4020458 - 22 Apr 2014
Cited by 12 | Viewed by 6060
Abstract
Chaperonin GroEL is a complex oligomeric heat shock protein (Hsp60) assisting the correct folding and assembly of other proteins in the cell. An intriguing question is how GroEL folds itself. According to the literature, GroEL reassembly is dependent on chaperonin ligands and solvent [...] Read more.
Chaperonin GroEL is a complex oligomeric heat shock protein (Hsp60) assisting the correct folding and assembly of other proteins in the cell. An intriguing question is how GroEL folds itself. According to the literature, GroEL reassembly is dependent on chaperonin ligands and solvent composition. Here we demonstrate dependence of GroEL reassembly efficiency on concentrations of the essential factors (Mg2+, ADP, ATP, GroES, ammonium sulfate, NaCl and glycerol). Besides, kinetics of GroEL oligomerization in various conditions was monitored by the light scattering technique and proved to be two-exponential, which suggested accumulation of a certain oligomeric intermediate. This intermediate was resolved as a heptamer by nondenaturing blue electrophoresis of GroEL monomers during their assembly in the presence of both Mg-ATP and co-chaperonin GroES. Presumably, this intermediate heptamer plays a key role in formation of the GroEL tetradecameric particle. The role of co-chaperonin GroES (Hsp10) in GroEL assembly is also discussed. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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1628 KiB  
Article
Similar Structures to the E-to-H Helix Unit in the Globin-Like Fold are Found in Other Helical Folds
by Masanari Matsuoka, Aoi Fujita, Yosuke Kawai and Takeshi Kikuchi
Biomolecules 2014, 4(1), 268-288; https://doi.org/10.3390/biom4010268 - 27 Feb 2014
Cited by 7 | Viewed by 8136
Abstract
A protein in the globin-like fold contains six alpha-helices, A, B, E, F, G and H. Among them, the E-to-H helix unit (E, F, G and H helices) forms a compact structure. In this study, we searched similar structures to the E-to-H helix [...] Read more.
A protein in the globin-like fold contains six alpha-helices, A, B, E, F, G and H. Among them, the E-to-H helix unit (E, F, G and H helices) forms a compact structure. In this study, we searched similar structures to the E-to-H helix of leghomoglobin in the whole protein structure space using the Dali program. Several similar structures were found in other helical folds, such as KaiA/RbsU domain and Type III secretion system domain. These observations suggest that the E-to-H helix unit may be a common subunit in the whole protein 3D structure space. In addition, the common conserved hydrophobic residues were found among the similar structures to the E-to-H helix unit. Hydrophobic interactions between the conserved residues may stabilize the 3D structures of the unit. We also predicted the possible compact regions of the units using the average distance method. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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1373 KiB  
Article
Molecular Dynamics Simulations Capture the Misfolding of the Bovine Prion Protein at Acidic pH
by Chin Jung Cheng and Valerie Daggett
Biomolecules 2014, 4(1), 181-201; https://doi.org/10.3390/biom4010181 - 10 Feb 2014
Cited by 22 | Viewed by 9216
Abstract
Bovine spongiform encephalopathy (BSE), or mad cow disease, is a fatal neurodegenerative disease that is transmissible to humans and that is currently incurable. BSE is caused by the prion protein (PrP), which adopts two conformers; PrPC is the native innocuous form, which [...] Read more.
Bovine spongiform encephalopathy (BSE), or mad cow disease, is a fatal neurodegenerative disease that is transmissible to humans and that is currently incurable. BSE is caused by the prion protein (PrP), which adopts two conformers; PrPC is the native innocuous form, which is α-helix rich; and PrPSc is the β-sheet rich misfolded form, which is infectious and forms neurotoxic species. Acidic pH induces the conversion of PrPC to PrPSc. We have performed molecular dynamics simulations of bovine PrP at various pH regimes. An acidic pH environment induced conformational changes that were not observed in neutral pH simulations. Putative misfolded structures, with nonnative β-strands formed in the flexible N-terminal domain, were found in acidic pH simulations. Two distinct pathways were observed for the formation of nonnative β-strands: at low pH, hydrophobic contacts with M129 nucleated the nonnative β-strand; at mid-pH, polar contacts involving Q168 and D178 facilitated the formation of a hairpin at the flexible N-terminus. These mid- and low pH simulations capture the process of nonnative β-strand formation, thereby improving our understanding of how PrPC misfolds into the β-sheet rich PrPSc and how pH factors into the process. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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567 KiB  
Article
Reconstructing Protein Structures by Neural Network Pairwise Interaction Fields and Iterative Decoy Set Construction
by Claudio Mirabello, Alessandro Adelfio and Gianluca Pollastri
Biomolecules 2014, 4(1), 160-180; https://doi.org/10.3390/biom4010160 - 10 Feb 2014
Cited by 2 | Viewed by 6772
Abstract
Predicting the fold of a protein from its amino acid sequence is one of the grand problems in computational biology. While there has been progress towards a solution, especially when a protein can be modelled based on one or more known structures (templates), [...] Read more.
Predicting the fold of a protein from its amino acid sequence is one of the grand problems in computational biology. While there has been progress towards a solution, especially when a protein can be modelled based on one or more known structures (templates), in the absence of templates, even the best predictions are generally much less reliable. In this paper, we present an approach for predicting the three-dimensional structure of a protein from the sequence alone, when templates of known structure are not available. This approach relies on a simple reconstruction procedure guided by a novel knowledge-based evaluation function implemented as a class of artificial neural networks that we have designed: Neural Network Pairwise Interaction Fields (NNPIF). This evaluation function takes into account the contextual information for each residue and is trained to identify native-like conformations from non-native-like ones by using large sets of decoys as a training set. The training set is generated and then iteratively expanded during successive folding simulations. As NNPIF are fast at evaluating conformations, thousands of models can be processed in a short amount of time, and clustering techniques can be adopted for model selection. Although the results we present here are very preliminary, we consider them to be promising, with predictions being generated at state-of-the-art levels in some of the cases. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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307 KiB  
Article
A Firefly-Inspired Method for Protein Structure Prediction in Lattice Models
by Brian Maher, Andreas A. Albrecht, Martin Loomes, Xin-She Yang and Kathleen Steinhöfel
Biomolecules 2014, 4(1), 56-75; https://doi.org/10.3390/biom4010056 - 07 Jan 2014
Cited by 25 | Viewed by 8568
Abstract
We introduce a Firefly-inspired algorithmic approach for protein structure prediction over two different lattice models in three-dimensional space. In particular, we consider three-dimensional cubic and three-dimensional face-centred-cubic (FCC) lattices. The underlying energy models are the Hydrophobic-Polar (H-P) model, the Miyazawa–Jernigan (M-J) model and [...] Read more.
We introduce a Firefly-inspired algorithmic approach for protein structure prediction over two different lattice models in three-dimensional space. In particular, we consider three-dimensional cubic and three-dimensional face-centred-cubic (FCC) lattices. The underlying energy models are the Hydrophobic-Polar (H-P) model, the Miyazawa–Jernigan (M-J) model and a related matrix model. The implementation of our approach is tested on ten H-P benchmark problems of a length of 48 and ten M-J benchmark problems of a length ranging from 48 until 61. The key complexity parameter we investigate is the total number of objective function evaluations required to achieve the optimum energy values for the H-P model or competitive results in comparison to published values for the M-J model. For H-P instances and cubic lattices, where data for comparison are available, we obtain an average speed-up over eight instances of 2.1, leaving out two extreme values (otherwise, 8.8). For six M-J instances, data for comparison are available for cubic lattices and runs with a population size of 100, where, a priori, the minimum free energy is a termination criterion. The average speed-up over four instances is 1.2 (leaving out two extreme values, otherwise 1.1), which is achieved for a population size of only eight instances. The present study is a test case with initial results for ad hoc parameter settings, with the aim of justifying future research on larger instances within lattice model settings, eventually leading to the ultimate goal of implementations for off-lattice models. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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6685 KiB  
Article
The Role of Non-Native Interactions in the Folding of Knotted Proteins: Insights from Molecular Dynamics Simulations
by Roberto Covino, Tatjana Škrbić, Silvio A Beccara, Pietro Faccioli and Cristian Micheletti
Biomolecules 2014, 4(1), 1-19; https://doi.org/10.3390/biom4010001 - 24 Dec 2013
Cited by 26 | Viewed by 7301
Abstract
For several decades, the presence of knots in naturally-occurring proteins was largely ruled out a priori for its supposed incompatibility with the efficiency and robustness of folding processes. For this very same reason, the later discovery of several unrelated families of knotted proteins [...] Read more.
For several decades, the presence of knots in naturally-occurring proteins was largely ruled out a priori for its supposed incompatibility with the efficiency and robustness of folding processes. For this very same reason, the later discovery of several unrelated families of knotted proteins motivated researchers to look into the physico-chemical mechanisms governing the concerted sequence of folding steps leading to the consistent formation of the same knot type in the same protein location. Besides experiments, computational studies are providing considerable insight into these mechanisms. Here, we revisit a number of such recent investigations within a common conceptual and methodological framework. By considering studies employing protein models with different structural resolution (coarse-grained or atomistic) and various force fields (from pure native-centric to realistic atomistic ones), we focus on the role of native and non-native interactions. For various unrelated instances of knotted proteins, non-native interactions are shown to be very important for favoring the emergence of conformations primed for successful self-knotting events. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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1336 KiB  
Article
Control of Collagen Stability and Heterotrimer Specificity through Repulsive Electrostatic Interactions
by Avanish S. Parmar, Mihir Joshi, Patrick L. Nosker, Nida F. Hasan and Vikas Nanda
Biomolecules 2013, 3(4), 986-996; https://doi.org/10.3390/biom3040986 - 06 Dec 2013
Cited by 7 | Viewed by 6482
Abstract
Charge-pair interactions between acidic and basic residues on the surface of collagen can promote stability as well as control specificity of molecular recognition. Heterotrimeric collagen peptides have been engineered de novo using either rational or computational methods, which in both cases optimize networks [...] Read more.
Charge-pair interactions between acidic and basic residues on the surface of collagen can promote stability as well as control specificity of molecular recognition. Heterotrimeric collagen peptides have been engineered de novo using either rational or computational methods, which in both cases optimize networks of favorable charge-pair interactions in the target structure. Less understood is the role of electrostatic repulsion between groups of like charge in destabilizing structure or directing molecular recognition. To study this, we apply a “charge crowding” approach, where repulsive interactions between multiple aspartate side chains are found to destabilize the homotrimer states in triple helical peptide system and can be utilized to promote the formation of heterotrimers. Neutralizing surface charge by increasing salt concentration or decreasing pH can enhance homotrimer stability, confirming the role of charge crowding on the destabilization of homotrimers via electrostatic repulsion. Charge crowding may be used in conjunction with other approaches to create specific collagen heterotrimers. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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961 KiB  
Article
Unfolding Thermodynamics of Cysteine-Rich Proteins and Molecular Thermal-Adaptation of Marine Ciliates
by Giorgia Cazzolli, Tatjana Škrbić, Graziano Guella and Pietro Faccioli
Biomolecules 2013, 3(4), 967-985; https://doi.org/10.3390/biom3040967 - 18 Nov 2013
Cited by 5 | Viewed by 6186
Abstract
Euplotes nobilii and Euplotes raikovi are phylogenetically closely allied species of marine ciliates, living in polar and temperate waters, respectively. Their evolutional relation and the sharply different temperatures of their natural environments make them ideal organisms to investigate thermal-adaptation. We perform a comparative [...] Read more.
Euplotes nobilii and Euplotes raikovi are phylogenetically closely allied species of marine ciliates, living in polar and temperate waters, respectively. Their evolutional relation and the sharply different temperatures of their natural environments make them ideal organisms to investigate thermal-adaptation. We perform a comparative study of the thermal unfolding of disulfide-rich protein pheromones produced by these ciliates. Recent circular dichroism (CD) measurements have shown that the two psychrophilic (E. nobilii) and mesophilic (E. raikovi) protein families are characterized by very different melting temperatures, despite their close structural homology. The enhanced thermal stability of the E. raikovi pheromones is realized notwithstanding the fact that these proteins form, as a rule, a smaller number of disulfide bonds. We perform Monte Carlo (MC) simulations in a structure-based coarse-grained (CG) model to show that the higher stability of the E. raikovi pheromones is due to the lower locality of the disulfide bonds, which yields a lower entropy increase in the unfolding process. Our study suggests that the higher stability of the mesophilic E. raikovi phermones is not mainly due to the presence of a strongly hydrophobic core, as it was proposed in the literature. In addition, we argue that the molecular adaptation of these ciliates may have occurred from cold to warm, and not from warm to cold. To provide a testable prediction, we identify a point-mutation of an E. nobilii pheromone that should lead to an unfolding temperature typical of that of E. raikovi pheromones. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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949 KiB  
Article
Variation in the Subcellular Localization and Protein Folding Activity among Arabidopsis thaliana Homologs of Protein Disulfide Isomerase
by Christen Y. L. Yuen, Kristie O. Matsumoto and David A. Christopher
Biomolecules 2013, 3(4), 848-869; https://doi.org/10.3390/biom3040848 - 21 Oct 2013
Cited by 23 | Viewed by 8460
Abstract
Protein disulfide isomerases (PDIs) catalyze the formation, breakage, and rearrangement of disulfide bonds to properly fold nascent polypeptides within the endoplasmic reticulum (ER). Classical animal and yeast PDIs possess two catalytic thioredoxin-like domains (a, a′) and two non-catalytic domains ( [...] Read more.
Protein disulfide isomerases (PDIs) catalyze the formation, breakage, and rearrangement of disulfide bonds to properly fold nascent polypeptides within the endoplasmic reticulum (ER). Classical animal and yeast PDIs possess two catalytic thioredoxin-like domains (a, a′) and two non-catalytic domains (b, b′), in the order a-b-b′-a′. The model plant, Arabidopsis thaliana, encodes 12 PDI-like proteins, six of which possess the classical PDI domain arrangement (AtPDI1 through AtPDI6). Three additional AtPDIs (AtPDI9, AtPDI10, AtPDI11) possess two thioredoxin domains, but without intervening b-b′ domains. C-terminal green fluorescent protein (GFP) fusions to each of the nine dual-thioredoxin PDI homologs localized predominantly to the ER lumen when transiently expressed in protoplasts. Additionally, expression of AtPDI9:GFP-KDEL and AtPDI10: GFP-KDDL was associated with the formation of ER bodies. AtPDI9, AtPDI10, and AtPDI11 mediated the oxidative folding of alkaline phosphatase when heterologously expressed in the Escherichia coli protein folding mutant, dsbA−. However, only three classical AtPDIs (AtPDI2, AtPDI5, AtPDI6) functionally complemented dsbA−. Interestingly, chemical inducers of the ER unfolded protein response were previously shown to upregulate most of the AtPDIs that complemented dsbA−. The results indicate that Arabidopsis PDIs differ in their localization and protein folding activities to fulfill distinct molecular functions in the ER. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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Review

Jump to: Research

5389 KiB  
Review
Local Order in the Unfolded State: Conformational Biases and Nearest Neighbor Interactions
by Siobhan Toal and Reinhard Schweitzer-Stenner
Biomolecules 2014, 4(3), 725-773; https://doi.org/10.3390/biom4030725 - 24 Jul 2014
Cited by 52 | Viewed by 10703
Abstract
The discovery of Intrinsically Disordered Proteins, which contain significant levels of disorder yet perform complex biologically functions, as well as unwanted aggregation, has motivated numerous experimental and theoretical studies aimed at describing residue-level conformational ensembles. Multiple lines of evidence gathered over the last [...] Read more.
The discovery of Intrinsically Disordered Proteins, which contain significant levels of disorder yet perform complex biologically functions, as well as unwanted aggregation, has motivated numerous experimental and theoretical studies aimed at describing residue-level conformational ensembles. Multiple lines of evidence gathered over the last 15 years strongly suggest that amino acids residues display unique and restricted conformational preferences in the unfolded state of peptides and proteins, contrary to one of the basic assumptions of the canonical random coil model. To fully understand residue level order/disorder, however, one has to gain a quantitative, experimentally based picture of conformational distributions and to determine the physical basis underlying residue-level conformational biases. Here, we review the experimental, computational and bioinformatic evidence for conformational preferences of amino acid residues in (mostly short) peptides that can be utilized as suitable model systems for unfolded states of peptides and proteins. In this context particular attention is paid to the alleged high polyproline II preference of alanine. We discuss how these conformational propensities may be modulated by peptide solvent interactions and so called nearest-neighbor interactions. The relevance of conformational propensities for the protein folding problem and the understanding of IDPs is briefly discussed. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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675 KiB  
Review
Decoding F508del Misfolding in Cystic Fibrosis
by Xiaodong Robert Wang and Chenglong Li
Biomolecules 2014, 4(2), 498-509; https://doi.org/10.3390/biom4020498 - 06 May 2014
Cited by 12 | Viewed by 10035
Abstract
The functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR), a plasma membrane chloride channel, leads to the development of cystic fibrosis. The deletion of a phenylalanine at residue 508 (F508del) is the most common cause of CFTR misfolding leading to the [...] Read more.
The functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR), a plasma membrane chloride channel, leads to the development of cystic fibrosis. The deletion of a phenylalanine at residue 508 (F508del) is the most common cause of CFTR misfolding leading to the disease. The F508del misfolding originates in the first nucleotide-binding domain (NBD1), which induces a global conformational change in CFTR through NBD1’s interactions with other domains. Such global misfolding produces a mutant chloride channel that is impaired in exocytic trafficking, peripheral stability, and channel gating. The nature and atomic details of F508del misfolding have been subject to extensive research during the past decade. Current data support a central role for NBD1 in F508del misfolding and rescue. Many cis-acting NBD1 second-site mutations rescue F508del misfolding in the context of full-length CFTR. While some of these mutations appear to specifically counteract the F508del-induced misfolding, others release certain inherent conformational constraints of the human wild-type CFTR. Several small-molecule correctors were recently found to act on key interdomain interfaces of F508del CFTR. Potential rational approaches have been proposed in an attempt to develop highly effective small molecule modulators that improve the cell surface functional expression of F508del CFTR. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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554 KiB  
Review
Kinetics and Thermodynamics of Membrane Protein Folding
by Ernesto A. Roman and F. Luis González Flecha
Biomolecules 2014, 4(1), 354-373; https://doi.org/10.3390/biom4010354 - 18 Mar 2014
Cited by 22 | Viewed by 14180
Abstract
Understanding protein folding has been one of the great challenges in biochemistry and molecular biophysics. Over the past 50 years, many thermodynamic and kinetic studies have been performed addressing the stability of globular proteins. In comparison, advances in the membrane protein folding field [...] Read more.
Understanding protein folding has been one of the great challenges in biochemistry and molecular biophysics. Over the past 50 years, many thermodynamic and kinetic studies have been performed addressing the stability of globular proteins. In comparison, advances in the membrane protein folding field lag far behind. Although membrane proteins constitute about a third of the proteins encoded in known genomes, stability studies on membrane proteins have been impaired due to experimental limitations. Furthermore, no systematic experimental strategies are available for folding these biomolecules in vitro. Common denaturing agents such as chaotropes usually do not work on helical membrane proteins, and ionic detergents have been successful denaturants only in few cases. Refolding a membrane protein seems to be a craftsman work, which is relatively straightforward for transmembrane β-barrel proteins but challenging for α-helical membrane proteins. Additional complexities emerge in multidomain membrane proteins, data interpretation being one of the most critical. In this review, we will describe some recent efforts in understanding the folding mechanism of membrane proteins that have been reversibly refolded allowing both thermodynamic and kinetic analysis. This information will be discussed in the context of current paradigms in the protein folding field. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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241 KiB  
Review
Detecting Selection on Protein Stability through Statistical Mechanical Models of Folding and Evolution
by Ugo Bastolla
Biomolecules 2014, 4(1), 291-314; https://doi.org/10.3390/biom4010291 - 07 Mar 2014
Cited by 13 | Viewed by 6380
Abstract
The properties of biomolecules depend both on physics and on the evolutionary process that formed them. These two points of view produce a powerful synergism. Physics sets the stage and the constraints that molecular evolution has to obey, and evolutionary theory helps in [...] Read more.
The properties of biomolecules depend both on physics and on the evolutionary process that formed them. These two points of view produce a powerful synergism. Physics sets the stage and the constraints that molecular evolution has to obey, and evolutionary theory helps in rationalizing the physical properties of biomolecules, including protein folding thermodynamics. To complete the parallelism, protein thermodynamics is founded on the statistical mechanics in the space of protein structures, and molecular evolution can be viewed as statistical mechanics in the space of protein sequences. In this review, we will integrate both points of view, applying them to detecting selection on the stability of the folded state of proteins. We will start discussing positive design, which strengthens the stability of the folded against the unfolded state of proteins. Positive design justifies why statistical potentials for protein folding can be obtained from the frequencies of structural motifs. Stability against unfolding is easier to achieve for longer proteins. On the contrary, negative design, which consists in destabilizing frequently formed misfolded conformations, is more difficult to achieve for longer proteins. The folding rate can be enhanced by strengthening short-range native interactions, but this requirement contrasts with negative design, and evolution has to trade-off between them. Finally, selection can accelerate functional movements by favoring low frequency normal modes of the dynamics of the native state that strongly correlate with the functional conformation change. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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452 KiB  
Review
Heavy Metals and Metalloids As a Cause for Protein Misfolding and Aggregation
by Markus J. Tamás, Sandeep K. Sharma, Sebastian Ibstedt, Therese Jacobson and Philipp Christen
Biomolecules 2014, 4(1), 252-267; https://doi.org/10.3390/biom4010252 - 25 Feb 2014
Cited by 330 | Viewed by 16481
Abstract
While the toxicity of metals and metalloids, like arsenic, cadmium, mercury, lead and chromium, is undisputed, the underlying molecular mechanisms are not entirely clear. General consensus holds that proteins are the prime targets; heavy metals interfere with the physiological activity of specific, particularly [...] Read more.
While the toxicity of metals and metalloids, like arsenic, cadmium, mercury, lead and chromium, is undisputed, the underlying molecular mechanisms are not entirely clear. General consensus holds that proteins are the prime targets; heavy metals interfere with the physiological activity of specific, particularly susceptible proteins, either by forming a complex with functional side chain groups or by displacing essential metal ions in metalloproteins. Recent studies have revealed an additional mode of metal action targeted at proteins in a non-native state; certain heavy metals and metalloids have been found to inhibit the in vitro refolding of chemically denatured proteins, to interfere with protein folding in vivo and to cause aggregation of nascent proteins in living cells. Apparently, unfolded proteins with motile backbone and side chains are considerably more prone to engage in stable, pluridentate metal complexes than native proteins with their well-defined 3D structure. By interfering with the folding process, heavy metal ions and metalloids profoundly affect protein homeostasis and cell viability. This review describes how heavy metals impede protein folding and promote protein aggregation, how cells regulate quality control systems to protect themselves from metal toxicity and how metals might contribute to protein misfolding disorders. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
1232 KiB  
Review
Refolding Techniques for Recovering Biologically Active Recombinant Proteins from Inclusion Bodies
by Hiroshi Yamaguchi and Masaya Miyazaki
Biomolecules 2014, 4(1), 235-251; https://doi.org/10.3390/biom4010235 - 20 Feb 2014
Cited by 201 | Viewed by 26149
Abstract
Biologically active proteins are useful for studying the biological functions of genes and for the development of therapeutic drugs and biomaterials in a biotechnology industry. Overexpression of recombinant proteins in bacteria, such as Escherichia coli, often results in the formation of inclusion [...] Read more.
Biologically active proteins are useful for studying the biological functions of genes and for the development of therapeutic drugs and biomaterials in a biotechnology industry. Overexpression of recombinant proteins in bacteria, such as Escherichia coli, often results in the formation of inclusion bodies, which are protein aggregates with non-native conformations. As inclusion bodies contain relatively pure and intact proteins, protein refolding is an important process to obtain active recombinant proteins from inclusion bodies. However, conventional refolding methods, such as dialysis and dilution, are time consuming and, often, recovered yields of active proteins are low, and a trial-and-error process is required to achieve success. Recently, several approaches have been reported to refold these aggregated proteins into an active form. The strategies largely aim at reducing protein aggregation during the refolding procedure. This review focuses on protein refolding techniques using chemical additives and laminar flow in microfluidic chips for the efficient recovery of active proteins from inclusion bodies. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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654 KiB  
Review
Transient Non-Native Helix Formation during the Folding of β-Lactoglobulin
by Masamichi Ikeguchi
Biomolecules 2014, 4(1), 202-216; https://doi.org/10.3390/biom4010202 - 13 Feb 2014
Cited by 13 | Viewed by 7506
Abstract
In ideal proteins, only native interactions are stabilized step-by-step in a smooth funnel-like energy landscape. In real proteins, however, the transient formation of non-native structures is frequently observed. In this review, the transient formation of non-native structures is described using the non-native helix [...] Read more.
In ideal proteins, only native interactions are stabilized step-by-step in a smooth funnel-like energy landscape. In real proteins, however, the transient formation of non-native structures is frequently observed. In this review, the transient formation of non-native structures is described using the non-native helix formation during the folding of β-lactoglobulin as a prominent example. Although β-lactoglobulin is a predominantly β-sheet protein, it has been shown to form non-native helices during the early stage of folding. The location of non-native helices, their stabilization mechanism, and their role in the folding reaction are discussed. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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873 KiB  
Review
Misfolding of Amyloidogenic Proteins and Their Interactions with Membranes
by Annalisa Relini, Nadia Marano and Alessandra Gliozzi
Biomolecules 2014, 4(1), 20-55; https://doi.org/10.3390/biom4010020 - 27 Dec 2013
Cited by 22 | Viewed by 9005
Abstract
In this paper, we discuss amyloidogenic proteins, their misfolding, resulting structures, and interactions with membranes, which lead to membrane damage and subsequent cell death. Many of these proteins are implicated in serious illnesses such as Alzheimer’s disease and Parkinson’s disease. Misfolding of amyloidogenic [...] Read more.
In this paper, we discuss amyloidogenic proteins, their misfolding, resulting structures, and interactions with membranes, which lead to membrane damage and subsequent cell death. Many of these proteins are implicated in serious illnesses such as Alzheimer’s disease and Parkinson’s disease. Misfolding of amyloidogenic proteins leads to the formation of polymorphic oligomers and fibrils. Oligomeric aggregates are widely thought to be the toxic species, however, fibrils also play a role in membrane damage. We focus on the structure of these aggregates and their interactions with model membranes. Study of interactions of amlyoidogenic proteins with model and natural membranes has shown the importance of the lipid bilayer in protein misfolding and aggregation and has led to the development of several models for membrane permeabilization by the resulting amyloid aggregates. We discuss several of these models: formation of structured pores by misfolded amyloidogenic proteins, extraction of lipids, interactions with receptors in biological membranes, and membrane destabilization by amyloid aggregates perhaps analogous to that caused by antimicrobial peptides. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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873 KiB  
Review
Protein Stability, Folding and Misfolding in Human PGK1 Deficiency
by Giovanna Valentini, Maristella Maggi and Angel L. Pey
Biomolecules 2013, 3(4), 1030-1052; https://doi.org/10.3390/biom3041030 - 18 Dec 2013
Cited by 15 | Viewed by 8952
Abstract
Conformational diseases are often caused by mutations, altering protein folding and stability in vivo. We review here our recent work on the effects of mutations on the human phosphoglycerate kinase 1 (hPGK1), with a particular focus on thermodynamics and kinetics of protein [...] Read more.
Conformational diseases are often caused by mutations, altering protein folding and stability in vivo. We review here our recent work on the effects of mutations on the human phosphoglycerate kinase 1 (hPGK1), with a particular focus on thermodynamics and kinetics of protein folding and misfolding. Expression analyses and in vitro biophysical studies indicate that disease-causing mutations enhance protein aggregation propensity. We found a strong correlation among protein aggregation propensity, thermodynamic stability, cooperativity and dynamics. Comparison of folding and unfolding properties with previous reports in PGKs from other species suggests that hPGK1 is very sensitive to mutations leading to enhance protein aggregation through changes in protein folding cooperativity and the structure of the relevant denaturation transition state for aggregation. Overall, we provide a mechanistic framework for protein misfolding of hPGK1, which is insightful to develop new therapeutic strategies aimed to target native state stability and foldability in hPGK1 deficient patients. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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501 KiB  
Review
Toxin Instability and Its Role in Toxin Translocation from the Endoplasmic Reticulum to the Cytosol
by Ken Teter
Biomolecules 2013, 3(4), 997-1029; https://doi.org/10.3390/biom3040997 - 10 Dec 2013
Cited by 18 | Viewed by 7272
Abstract
AB toxins enter a host cell by receptor-mediated endocytosis. The catalytic A chain then crosses the endosome or endoplasmic reticulum (ER) membrane to reach its cytosolic target. Dissociation of the A chain from the cell-binding B chain occurs before or during translocation to [...] Read more.
AB toxins enter a host cell by receptor-mediated endocytosis. The catalytic A chain then crosses the endosome or endoplasmic reticulum (ER) membrane to reach its cytosolic target. Dissociation of the A chain from the cell-binding B chain occurs before or during translocation to the cytosol, and only the A chain enters the cytosol. In some cases, AB subunit dissociation is facilitated by the unique physiology and function of the ER. The A chains of these ER-translocating toxins are stable within the architecture of the AB holotoxin, but toxin disassembly results in spontaneous or assisted unfolding of the isolated A chain. This unfolding event places the A chain in a translocation-competent conformation that promotes its export to the cytosol through the quality control mechanism of ER-associated degradation. A lack of lysine residues for ubiquitin conjugation protects the exported A chain from degradation by the ubiquitin-proteasome system, and an interaction with host factors allows the cytosolic toxin to regain a folded, active state. The intrinsic instability of the toxin A chain thus influences multiple steps of the intoxication process. This review will focus on the host–toxin interactions involved with A chain unfolding in the ER and A chain refolding in the cytosol. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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