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Special Issue "Intrinsically Disordered Proteins in the Norm and Pathology: In-Silico Perspective"

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

Deadline for manuscript submissions: closed (31 December 2017)

Special Issue Editors

Guest Editor
Prof. Dr. Lukasz Kurgan

Department of Computer Science, Virginia Commonwealth University, Richmond, VA, USA
Website | E-Mail
Phone: +1 780-492-5488
Fax: +1 780-492-1811
Interests: Structural bioinformatics; protein-ligand interactions; intrinsic disorder; structural genomics
Guest Editor
Assoc. Prof. Dr. Vladimir N. Uversky

Molecular Medicine, University of South Florida, Tampa, USA
Website | E-Mail
Interests: intrinsically disordered proteins; protein folding; protein misfolding; partially folded proteins; protein aggregation; protein structure; protein function; protein biophysics; protein bioinformatics; conformational diseases; protein–ligand interactions; protein–protein interactions

Special Issue Information

Dear Colleagues,

Intrinsically disordered proteins (IDPs) and hybrid proteins that have ordered domains and intrinsically disordered regions (IDRs) are proteins and regions that do not have stable tertiary and/or secondary structures under physiological conditions. They are very common in nature and functionally complement ordered proteins. Despite being devoid of unique structures, IDPs/IDPRs are important players in regulation, signaling, and control, they engage in binding to multiple partners, and participate in one-to-many and many-to-one signaling. Being crucial controllers of numerous biological processes, IDPs/IDPRs are tightly controlled and precisely tuned themselves by multiple means, including alternative splicing and posttranslational modifications. There are numerous examples showing that when de-regulated and uncontrolled, various IDPs/IDPRs are involved in the development of various pathological conditions, such as amyloidoses, cancers, cardiovascular disease, diabetes, genetic diseases, neurodegenerative diseases, psychiatric diseases, and many other maladies. IDPs/IDPRs are nowadays being considered as new and very promising drug targets.

Computational methods for prediction and analysis of disorder from protein sequences, for performing analysis of protein dynamics, as well as for finding correlation between intrinsic disorder and various human diseases, have emerged as viable approaches greatly enhancing research capabilities of modern protein scientists. These methods find numerous important applications in functional and structural proteomics. We invite you to contribute articles that describe computational methods for predicting IDPs/IDPRs, their functions and pathological associations, and the applications of computational methods to characterize the abundance, functional roles, conformational dynamics, and other characteristic features of intrinsically disordered proteins. Articles that include an experimental component are also encouraged.

Dr. Lukasz Kurgan
Dr. Vladimir N. Uversky
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access 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 1800 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

  • intrinsic disorder
  • intrinsically disordered proteins
  • intrinsically disordered regions
  • computational prediction
  • function of intrinsic disorder
  • protein-protein interactions
  • posttranslational modifications
  • alternative splicing
  • induced folding
  • protein misfolding
  • protein aggregation
  • gain of pathological function
  • point mutation
  • proteostasis
  • proteinopathies
  • drug discovery

Related Special Issue

Published Papers (6 papers)

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Research

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Open AccessArticle Discovery of Cryoprotective Activity in Human Genome-Derived Intrinsically Disordered Proteins
Int. J. Mol. Sci. 2018, 19(2), 401; https://doi.org/10.3390/ijms19020401
Received: 20 December 2017 / Revised: 17 January 2018 / Accepted: 22 January 2018 / Published: 30 January 2018
PDF Full-text (2158 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Intrinsically disordered proteins (IDPs) are an emerging phenomenon. They may have a high degree of flexibility in their polypeptide chains, which lack a stable 3D structure. Although several biological functions of IDPs have been proposed, their general function is not known. The only
[...] Read more.
Intrinsically disordered proteins (IDPs) are an emerging phenomenon. They may have a high degree of flexibility in their polypeptide chains, which lack a stable 3D structure. Although several biological functions of IDPs have been proposed, their general function is not known. The only finding related to their function is the genetically conserved YSK2 motif present in plant dehydrins. These proteins were shown to be IDPs with the YSK2 motif serving as a core region for the dehydrins’ cryoprotective activity. Here we examined the cryoprotective activity of randomly selected IDPs toward the model enzyme lactate dehydrogenase (LDH). All five IDPs that were examined were in the range of 35–45 amino acid residues in length and were equally potent at a concentration of 50 μg/mL, whereas folded proteins, the PSD-95/Dlg/ZO-1 (PDZ) domain, and lysozymes had no potency. We further examined their cryoprotective activity toward glutathione S-transferase as an example of the other enzyme, and toward enhanced green fluorescent protein as a non-enzyme protein example. We further examined the lyophilization protective activity of the peptides toward LDH, which revealed that some IDPs showed a higher activity than that of bovine serum albumin (BSA). Based on these observations, we propose that cryoprotection is a general feature of IDPs. Our findings may become a clue to various industrial applications of IDPs in the future. Full article
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Open AccessArticle Understanding the Role of Intrinsic Disorder of Viral Proteins in the Oncogenicity of Different Types of HPV
Int. J. Mol. Sci. 2018, 19(1), 198; https://doi.org/10.3390/ijms19010198
Received: 19 December 2017 / Revised: 6 January 2018 / Accepted: 7 January 2018 / Published: 9 January 2018
PDF Full-text (5559 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Intrinsic disorder is very important in the biological function of several proteins, and is directly linked to their foldability during interaction with their targets. There is a close relationship between the intrinsically disordered proteins and the process of carcinogenesis involving viral pathogens. Among
[...] Read more.
Intrinsic disorder is very important in the biological function of several proteins, and is directly linked to their foldability during interaction with their targets. There is a close relationship between the intrinsically disordered proteins and the process of carcinogenesis involving viral pathogens. Among these pathogens, we have highlighted the human papillomavirus (HPV) in this study. HPV is currently among the most common sexually transmitted infections, besides being the cause of several types of cancer. HPVs are divided into two groups, called high- and low-risk, based on their oncogenic potential. The high-risk HPV E6 protein has been the target of much research, in seeking treatments against HPV, due to its direct involvement in the process of cell cycle control. To understand the role of intrinsic disorder of the viral proteins in the oncogenic potential of different HPV types, the structural characteristics of intrinsically disordered regions of high and low-risk HPV E6 proteins were analyzed. In silico analyses of primary sequences, prediction of tertiary structures, and analyses of molecular dynamics allowed the observation of the behavior of such disordered regions in these proteins, thereby proving a direct relationship of structural variation with the degree of oncogenicity of HPVs. The results obtained may contribute to the development of new therapies, targeting the E6 oncoprotein, for the treatment of HPV-associated diseases. Full article
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Open AccessArticle InSiDDe: A Server for Designing Artificial Disordered Proteins
Int. J. Mol. Sci. 2018, 19(1), 91; https://doi.org/10.3390/ijms19010091
Received: 24 November 2017 / Revised: 21 December 2017 / Accepted: 22 December 2017 / Published: 29 December 2017
PDF Full-text (4181 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
InSiDDe (In Silico Disorder Design) is a program for the in silico design of intrinsically disordered proteins of desired length and disorder probability. The latter is assessed using IUPred and spans values ranging from 0.55 to 0.95 with 0.05 increments. One to ten
[...] Read more.
InSiDDe (In Silico Disorder Design) is a program for the in silico design of intrinsically disordered proteins of desired length and disorder probability. The latter is assessed using IUPred and spans values ranging from 0.55 to 0.95 with 0.05 increments. One to ten artificial sequences per query, each made of 50 to 200 residues, can be generated by InSiDDe. We describe the rationale used to set up InSiDDe and show that an artificial sequence of 100 residues with an IUPred score of 0.6 designed by InSiDDe could be recombinantly expressed in E. coli at high levels without degradation when fused to a natural molecular recognition element (MoRE). In addition, the artificial fusion protein exhibited the expected behavior in terms of binding modulation of the specific partner recognized by the MoRE. To the best of our knowledge, InSiDDe is the first publicly available software for the design of intrinsically disordered protein (IDP) sequences. InSiDDE is publicly available online. Full article
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Open AccessArticle Functional Analysis of Human Hub Proteins and Their Interactors Involved in the Intrinsic Disorder-Enriched Interactions
Int. J. Mol. Sci. 2017, 18(12), 2761; https://doi.org/10.3390/ijms18122761
Received: 1 November 2017 / Revised: 13 December 2017 / Accepted: 15 December 2017 / Published: 19 December 2017
PDF Full-text (3838 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Some of the intrinsically disordered proteins and protein regions are promiscuous interactors that are involved in one-to-many and many-to-one binding. Several studies have analyzed enrichment of intrinsic disorder among the promiscuous hub proteins. We extended these works by providing a detailed functional characterization
[...] Read more.
Some of the intrinsically disordered proteins and protein regions are promiscuous interactors that are involved in one-to-many and many-to-one binding. Several studies have analyzed enrichment of intrinsic disorder among the promiscuous hub proteins. We extended these works by providing a detailed functional characterization of the disorder-enriched hub protein-protein interactions (PPIs), including both hubs and their interactors, and by analyzing their enrichment among disease-associated proteins. We focused on the human interactome, given its high degree of completeness and relevance to the analysis of the disease-linked proteins. We quantified and investigated numerous functional and structural characteristics of the disorder-enriched hub PPIs, including protein binding, structural stability, evolutionary conservation, several categories of functional sites, and presence of over twenty types of posttranslational modifications (PTMs). We showed that the disorder-enriched hub PPIs have a significantly enlarged number of disordered protein binding regions and long intrinsically disordered regions. They also include high numbers of targeting, catalytic, and many types of PTM sites. We empirically demonstrated that these hub PPIs are significantly enriched among 11 out of 18 considered classes of human diseases that are associated with at least 100 human proteins. Finally, we also illustrated how over a dozen specific human hubs utilize intrinsic disorder for their promiscuous PPIs. Full article
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Review

Jump to: Research

Open AccessReview How Do We Study the Dynamic Structure of Unstructured Proteins: A Case Study on Nopp140 as an Example of a Large, Intrinsically Disordered Protein
Int. J. Mol. Sci. 2018, 19(2), 381; https://doi.org/10.3390/ijms19020381
Received: 4 January 2018 / Revised: 22 January 2018 / Accepted: 23 January 2018 / Published: 27 January 2018
PDF Full-text (3693 KB) | HTML Full-text | XML Full-text
Abstract
Intrinsically disordered proteins (IDPs) represent approximately 30% of the human genome and play key roles in cell proliferation and cellular signaling by modulating the function of target proteins via protein–protein interactions. In addition, IDPs are involved in various human disorders, such as cancer,
[...] Read more.
Intrinsically disordered proteins (IDPs) represent approximately 30% of the human genome and play key roles in cell proliferation and cellular signaling by modulating the function of target proteins via protein–protein interactions. In addition, IDPs are involved in various human disorders, such as cancer, neurodegenerative diseases, and amyloidosis. To understand the underlying molecular mechanism of IDPs, it is important to study their structural features during their interactions with target proteins. However, conventional biochemical and biophysical methods for analyzing proteins, such as X-ray crystallography, have difficulty in characterizing the features of IDPs because they lack an ordered three-dimensional structure. Here, we present biochemical and biophysical studies on nucleolar phosphoprotein 140 (Nopp140), which mostly consists of disordered regions, during its interaction with casein kinase 2 (CK2), which plays a central role in cell growth. Surface plasmon resonance and electron paramagnetic resonance studies were performed to characterize the interaction between Nopp140 and CK2. A single-molecule fluorescence resonance energy transfer study revealed conformational change in Nopp140 during its interaction with CK2. These studies on Nopp140 can provide a good model system for understanding the molecular function of IDPs. Full article
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Open AccessFeature PaperReview Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology
Int. J. Mol. Sci. 2018, 19(2), 336; https://doi.org/10.3390/ijms19020336
Received: 12 November 2017 / Revised: 14 January 2018 / Accepted: 16 January 2018 / Published: 24 January 2018
Cited by 1 | PDF Full-text (8532 KB) | HTML Full-text | XML Full-text
Abstract
Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs), which are at the center of Alzheimer’s and Parkinson’s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and
[...] Read more.
Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs), which are at the center of Alzheimer’s and Parkinson’s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer’s and Parkinson’s diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β and α-synuclein in relation to the pathologies of Alzheimer’s and Parkinson’s diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer’s and Parkinson’s diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid-β and α-synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid-β and α-synuclein, such as β-structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer’s and Parkinson’s diseases. This information represents an important foundation for the successful and efficient drug design studies. Full article
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