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Protein Folding and Misfolding ---- Structure and Functions

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

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 35328

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Special Issue Editors

Prof. Dr. Victor Muñoz

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Guest Editor

Director NSF-CREST Center for Cellular and Biomolecular Machines (CCBM), University of California Merced, 5200 North Lake Road, Merced, CA 95340, USA
Interests: molecular biophysics; quantitative and synthetic biology; protein engineering; protein folding, binding and function; protein–DNA interactions; molecular mechanisms of transcription; single molecule fluorescence; statistical mechanics; computational chemistry and biology; optical spectroscopy; nuclear magnetic resonance spectroscopy (NMR); atomic force microscopy (AFM); laser spectroscopy and ultrafast kinetics

Prof. Dr. Stefano Gianni

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Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
Interests: protein folding; protein dynamics and disorder; protein-protein recognition
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nearly all biological processes rely on the conformational states of interacting macromolecules. It is, therefore, not surprising that the study of protein folding and misfolding has played a central role in chemistry and biology. In particular, substantial experimental and theoretical efforts have been devoted to understanding the general rules of folding, as well as to deciphering the mechanisms that lead to misfolding and related diseases. Furthermore, the discovery that a large fraction of the proteome is essentially disordered, while being fully functional, has revolutionized our comprehension of the structure–function relationships, posing the description of intrinsically disordered proteins as a key problem in modern science.

This Special Issue focuses on recent studies that contribute to our understanding of protein folding and misfolding, as well as on the role of intrinsic disorder in protein functions. Original research articles and reviews on these and related topics are welcome in this Special Issue.

Prof. Dr. Victor Muñoz
Prof. Dr. Stefano Gianni
Guest Editors

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

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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;
chaperones;
foldases;
energy landscape;
molecular dynamics simulation;
chemical kinetics;
energy barriers;
down-hill folding;
protein misfolding;
protein unfolding;
amyloid structure;
degenerative diseases;
proteopathy;
oligomer toxicity;
intrinsic disorder;
intrinsically disordered proteins;
folding upon binding

Published Papers (11 papers)

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Research

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24 pages, 9597 KiB

Open AccessArticle

On the Dependence of Prion and Amyloid Structure on the Folding Environment

by Irena Roterman, Katarzyna Stapor, Krzysztof Gądek, Tomasz Gubała, Piotr Nowakowski, Piotr Fabian and Leszek Konieczny

Int. J. Mol. Sci. 2021, 22(24), 13494; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413494 - 16 Dec 2021

Cited by 7 | Viewed by 1719

Abstract

Currently available analyses of amyloid proteins reveal the necessity of the existence of radical structural changes in amyloid transformation processes. The analysis carried out in this paper based on the model called fuzzy oil drop (FOD) and its modified form (FOD-M) allows quantifying the role of the environment, particularly including the aquatic environment. The starting point and basis for the present presentation is the statement about the presence of two fundamentally different methods of organizing polypeptides into ordered conformations—globular proteins and amyloids. The present study shows the source of the differences between these two paths resulting from the specificity of the external force field coming from the environment, including the aquatic and hydrophobic one. The water environment expressed in the fuzzy oil drop model using the 3D Gauss function directs the folding process towards the construction of a micelle-like system with a hydrophobic core in the central part and the exposure of polarity on the surface. The hydrophobicity distribution of membrane proteins has the opposite characteristic: Exposure of hydrophobicity at the surface of the membrane protein with an often polar center (as in the case of ion channels) is expected. The structure of most proteins is influenced by a more or less modified force field generated by water through the appropriate presence of a non-polar (membrane-like) environment. The determination of the proportion of a factor different from polar water enables the assessment of the protein status by indicating factors favoring the structure it represents. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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15 pages, 15197 KiB

Open AccessArticle

Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations

by Lukas Schulig, Piotr Grabarczyk, Norman Geist, Martin Delin, Hannes Forkel, Martin Kulke, Mihaela Delcea, Christian A. Schmidt and Andreas Link

Int. J. Mol. Sci. 2021, 22(7), 3650; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073650 - 31 Mar 2021

Cited by 2 | Viewed by 2617

Abstract

Transcription factors play a crucial role in regulating biological processes such as cell growth, differentiation, organ development and cellular signaling. Within this group, proteins equipped with zinc finger motifs (ZFs) represent the largest family of sequence-specific DNA-binding transcription regulators. Numerous studies have proven the fundamental role of BCL11B for a variety of tissues and organs such as central nervous system, T cells, skin, teeth, and mammary glands. In a previous work we identified a novel atypical zinc finger domain (CCHC-ZF) which serves as a dimerization interface of BCL11B. This domain and formation of the dimer were shown to be critically important for efficient regulation of the BCL11B target genes and could therefore represent a promising target for novel drug therapies. Here, we report the structural basis for BCL11B–BCL11B interaction mediated by the N-terminal ZF domain. By combining structure prediction algorithms, enhanced sampling molecular dynamics and fluorescence resonance energy transfer (FRET) approaches, we identified amino acid residues indispensable for the formation of the single ZF domain and directly involved in forming the dimer interface. These findings not only provide deep insight into how BCL11B acquires its active structure but also represent an important step towards rational design or selection of potential inhibitors. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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18 pages, 5088 KiB

Open AccessArticle

Downhill, Ultrafast and Fast Folding Proteins Revised

by Mateusz Banach, Katarzyna Stapor, Leszek Konieczny, Piotr Fabian and Irena Roterman

Int. J. Mol. Sci. 2020, 21(20), 7632; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207632 - 15 Oct 2020

Cited by 17 | Viewed by 2346

Abstract

Research on the protein folding problem differentiates the protein folding process with respect to the duration of this process. The current structure encoded in sequence dogma seems to be clearly justified, especially in the case of proteins referred to as fast-folding, ultra-fast-folding or downhill. In the present work, an attempt to determine the characteristics of this group of proteins using fuzzy oil drop model is undertaken. According to the fuzzy oil drop model, a protein is a specific micelle composed of bi-polar molecules such as amino acids. Protein folding is regarded as a spherical micelle formation process. The presence of covalent peptide bonds between amino acids eliminates the possibility of free mutual arrangement of neighbors. An example would be the construction of co-micelles composed of more than one type of bipolar molecules. In the case of fast folding proteins, the amino acid sequence represents the optimal bipolarity system to generate a spherical micelle. In order to achieve the native form, it is enough to have an external force field provided by the water environment which directs the folding process towards the generation of a centric hydrophobic core. The influence of the external field can be expressed using the 3D Gaussian function which is a mathematical model of the folding process orientation towards the concentration of hydrophobic residues in the center with polar residues exposed on the surface. The set of proteins under study reveals a hydrophobicity distribution compatible with a 3D Gaussian distribution, taken as representing an idealized micelle-like distribution. The structure of the present hydrophobic core is also discussed in relation to the distribution of hydrophobic residues in a partially unfolded form. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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16 pages, 5783 KiB

Open AccessArticle

New Factors Enhancing the Reactivity of Cysteines in Molten Globule-Like Structures

by Giorgia Gambardella, Giada Cattani, Alessio Bocedi and Giorgio Ricci

Int. J. Mol. Sci. 2020, 21(18), 6949; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186949 - 22 Sep 2020

Cited by 9 | Viewed by 1881

Abstract

Protein cysteines often play crucial functional and structural roles, so they are emerging targets to design covalent thiol ligands that are able to modulate enzyme or protein functions. Some of these residues, especially those involved in enzyme mechanisms—including nucleophilic and reductive catalysis and thiol-disulfide exchange—display unusual hyper-reactivity; such a property is expected to result from a low pK_a and from a great accessibility to a given reagent. New findings and previous evidence clearly indicate that pK_a perturbations can only produce two–four-times increased reactivity at physiological pH values, far from the hundred and even thousand-times kinetic enhancements observed for some protein cysteines. The data from the molten globule-like structures of ribonuclease, lysozyme, bovine serum albumin and chymotrypsinogen identified new speeding agents, i.e., hydrophobic/electrostatic interactions and productive complex formations involving the protein and thiol reagent, which were able to confer exceptional reactivity to structural cysteines which were only intended to form disulfides. This study, for the first time, evaluates quantitatively the different contributions of pK_a and other factors to the overall reactivity. These findings may help to clarify the mechanisms that allow a rapid disulfide formation during the oxidative folding of many proteins. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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24 pages, 4008 KiB

Open AccessArticle

Insight into the Folding and Dimerization Mechanisms of the N-Terminal Domain from Human TDP-43

by Mirella Vivoli-Vega, Prandvera Guri, Fabrizio Chiti and Francesco Bemporad

Int. J. Mol. Sci. 2020, 21(17), 6259; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176259 - 29 Aug 2020

Cited by 12 | Viewed by 3312

Abstract

TAR DNA-binding protein 43 (TDP-43) is a 414-residue long nuclear protein whose deposition into intraneuronal insoluble inclusions has been associated with the onset of amyotrophic lateral sclerosis (ALS) and other diseases. This protein is physiologically a homodimer, and dimerization occurs through the N-terminal domain (NTD), with a mechanism on which a full consensus has not yet been reached. Furthermore, it has been proposed that this domain is able to affect the formation of higher molecular weight assemblies. Here, we purified this domain and carried out an unprecedented characterization of its folding/dimerization processes in solution. Exploiting a battery of biophysical approaches, ranging from FRET to folding kinetics, we identified a head-to-tail arrangement of the monomers within the dimer. We found that folding of NTD proceeds through the formation of a number of conformational states and two parallel pathways, while a subset of molecules refold slower, due to proline isomerism. The folded state appears to be inherently prone to form high molecular weight assemblies. Taken together, our results indicate that NTD is inherently plastic and prone to populate different conformations and dimeric/multimeric states, a structural feature that may enable this domain to control the assembly state of TDP-43. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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11 pages, 2079 KiB

Open AccessArticle

Real-Time 3D Imaging and Inhibition Analysis of Various Amyloid Aggregations Using Quantum Dots

by Xuguang Lin, Nuomin Galaqin, Reina Tainaka, Keiya Shimamori, Masahiro Kuragano, Taro Q. P. Noguchi and Kiyotaka Tokuraku

Int. J. Mol. Sci. 2020, 21(6), 1978; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21061978 - 13 Mar 2020

Cited by 10 | Viewed by 3647

Abstract

Amyloidosis refers to aggregates of protein that accumulate and are deposited as amyloid fibrils into plaques. When these are detected in organs, they are the main hallmark of Alzheimer’s disease, Parkinson’s disease, and other related diseases. Recent medical advances have shown that many precursors and proteins can induce amyloidosis even though the mechanism of amyloid aggregation and the relationship of these proteins to amyloidosis remains mostly unclear. In this study, we report the real-time 3D-imaging and inhibition analysis of amyloid β (Aβ), tau, and α-synuclein aggregation utilizing the affinity between quantum dots (QD) and amyloid aggregates. We successfully visualized these amyloid aggregations in real-time using fluorescence microscopy and confocal microscopy simply by adding commercially available QD. The observation by transmission electron microscopy (TEM) showed that QD particles bound to all amyloid fibrils. The 3D-imaging with QD revealed differences between amyloid aggregates composed of different amyloid peptides that could not be detected by TEM. We were also able to quantify the inhibition activities of these proteins by rosmarinic acid, which has high activity for Aβ aggregation, from fluorescence micrographs as half-maximal effective concentrations. These imaging techniques with QD serve as quick, easy, and powerful tools to understand amyloidosis and to discover drugs for therapies. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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11 pages, 1174 KiB

Open AccessArticle

Folding Rate Optimization Promotes Frustrated Interactions in Entangled Protein Structures

by Federico Norbiato, Flavio Seno, Antonio Trovato and Marco Baiesi

Int. J. Mol. Sci. 2020, 21(1), 213; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010213 - 27 Dec 2019

Cited by 6 | Viewed by 2308

Abstract

Many native structures of proteins accomodate complex topological motifs such as knots, lassos, and other geometrical entanglements. How proteins can fold quickly even in the presence of such topological obstacles is a debated question in structural biology. Recently, the hypothesis that energetic frustration might be a mechanism to avoid topological frustration has been put forward based on the empirical observation that loops involved in entanglements are stabilized by weak interactions between amino-acids at their extrema. To verify this idea, we use a toy lattice model for the folding of proteins into two almost identical structures, one entangled and one not. As expected, the folding time is longer when random sequences folds into the entangled structure. This holds also under an evolutionary pressure simulated by optimizing the folding time. It turns out that optmized protein sequences in the entangled structure are in fact characterized by frustrated interactions at the closures of entangled loops. This phenomenon is much less enhanced in the control case where the entanglement is not present. Our findings, which are in agreement with experimental observations, corroborate the idea that an evolutionary pressure shapes the folding funnel to avoid topological and kinetic traps. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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10 pages, 1460 KiB

Open AccessArticle

The Effect of Proline cis-trans Isomerization on the Folding of the C-Terminal SH2 Domain from p85

by Francesca Troilo, Francesca Malagrinò, Lorenzo Visconti, Angelo Toto and Stefano Gianni

Int. J. Mol. Sci. 2020, 21(1), 125; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010125 - 23 Dec 2019

Cited by 5 | Viewed by 2485

Abstract

SH2 domains are protein domains that modulate protein–protein interactions through a specific interaction with sequences containing phosphorylated tyrosines. In this work, we analyze the folding pathway of the C-terminal SH2 domain of the p85 regulatory subunit of the protein PI3K, which presents a proline residue in a cis configuration in the loop between the βE and βF strands. By employing single and double jump folding and unfolding experiments, we demonstrate the presence of an on-pathway intermediate that transiently accumulates during (un)folding. By comparing the kinetics of folding of the wild-type protein to that of a site-directed variant of C-SH2 in which the proline was replaced with an alanine, we demonstrate that this intermediate is dictated by the peptidyl prolyl cis-trans isomerization. The results are discussed in the light of previous work on the effect of peptidyl prolyl cis-trans isomerization on folding events. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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Review

Jump to: Research

14 pages, 9243 KiB

Open AccessReview

Transthyretin Misfolding, A Fatal Structural Pathogenesis Mechanism

by Jin-Beom Si, Bokyung Kim and Jin Hae Kim

Int. J. Mol. Sci. 2021, 22(9), 4429; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094429 - 23 Apr 2021

Cited by 17 | Viewed by 3475

Abstract

Transthyretin (TTR) is an essential transporter of a thyroid hormone and a holo-retinol binding protein, found abundantly in human plasma and cerebrospinal fluid. In addition, this protein is infamous for its amyloidogenic propensity, causing various amyloidoses in humans, such as senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. It has been known for over two decades that decreased stability of the native tetrameric conformation of TTR is the main cause of these diseases. Yet, mechanistic details on the amyloidogenic transformation of TTR were not clear until recent multidisciplinary investigations on various structural states of TTR. In this review, we discuss recent advancements in the structural understanding of TTR misfolding and amyloidosis processes. Special emphasis has been laid on the observations of novel structural features in various amyloidogenic species of TTR. In addition, proteolysis-induced fragmentation of TTR, a recently proposed mechanism facilitating TTR amyloidosis, has been discussed in light of its structural consequences and relevance to acknowledge the amyloidogenicity of TTR. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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10 pages, 1217 KiB

Open AccessReview

Double Mutant Cycles as a Tool to Address Folding, Binding, and Allostery

by Livia Pagano, Angelo Toto, Francesca Malagrinò, Lorenzo Visconti, Per Jemth and Stefano Gianni

Int. J. Mol. Sci. 2021, 22(2), 828; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020828 - 15 Jan 2021

Cited by 13 | Viewed by 2768

Abstract

Quantitative measurement of intramolecular and intermolecular interactions in protein structure is an elusive task, not easy to address experimentally. The phenomenon denoted ‘energetic coupling’ describes short- and long-range interactions between two residues in a protein system. A powerful method to identify and quantitatively characterize long-range interactions and allosteric networks in proteins or protein–ligand complexes is called double-mutant cycles analysis. In this review we describe the thermodynamic principles and basic equations that underlie the double mutant cycle methodology, its fields of application and latest employments, and caveats and pitfalls that the experimentalists must consider. In particular, we show how double mutant cycles can be a powerful tool to investigate allosteric mechanisms in protein binding reactions as well as elusive states in protein folding pathways. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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15 pages, 8004 KiB

Open AccessReview

Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways

by Esra Karatas and Marion Bouchecareilh

Int. J. Mol. Sci. 2020, 21(4), 1493; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041493 - 21 Feb 2020

Cited by 21 | Viewed by 7134

Abstract

Human cells express large amounts of different proteins continuously that must fold into well-defined structures that need to remain correctly folded and assemble in order to ensure their cellular and biological functions. The integrity of this protein balance/homeostasis, also named proteostasis, is maintained by the proteostasis network (PN). This integrated biological system, which comprises about 2000 proteins (chaperones, folding enzymes, degradation components), control and coordinate protein synthesis folding and localization, conformational maintenance, and degradation. This network is particularly challenged by mutations such as those found in genetic diseases, because of the inability of an altered peptide sequence to properly engage PN components that trigger misfolding and loss of function. Thus, deletions found in the ΔF508 variant of the Cystic Fibrosis (CF) transmembrane regulator (CFTR) triggering CF or missense mutations found in the Z variant of Alpha 1-Antitrypsin deficiency (AATD), leading to lung and liver diseases, can accelerate misfolding and/or generate aggregates. Conversely to CF variants, for which three correctors are already approved (ivacaftor, lumacaftor/ivacaftor, and most recently tezacaftor/ivacaftor), there are limited therapeutic options for AATD. Therefore, a more detailed understanding of the PN components governing AAT variant biogenesis and their manipulation by pharmacological intervention could delay, or even better, avoid the onset of AATD-related pathologies. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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