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Intrinsically Disordered Proteins (IDPs) 2.0
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Intrinsically Disordered Proteins (IDPs) 2.0

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

Deadline for manuscript submissions: closed (15 July 2023) | Viewed by 16591

Special Issue Editors

Dr. Josephine C. Ferreon

E-Mail Website
Guest Editor
Baylor College of Medicine, Department of Pharmacology and Chemical Biology, Houston, TX 77030, USA
Interests: NMR spectroscopy; intrinsically disordered proteins; stem cell biology; protein structure and function; post-translational modifications; macromolecular assembly; biomolecular phase transitions
Special Issues, Collections and Topics in MDPI journals
Dr. Allan Chris Ferreon

E-Mail Website
Guest Editor
Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA
Interests: single molecule biophysics; fluorescence spectroscopy; molecular mechanisms of neurodegenerative disorders; intrinsically disordered proteins; protein folding and misfolding; protein–ligand interactions; biomolecular phase transitions

Special Issue Information

Dear Colleagues,

The classic protein structure–function paradigm has shifted in this millennium with the emergence of a new class of proteins known as intrinsically disordered proteins (IDPs)—proteins that are either entirely unstructured or contain a significant region of disorder. Their function is linked to their conformational flexibility, with many IDPs acting as “hubs” that interact with multiple molecular binding partners to regulate biological functions such as transcription, signal transduction, and intracellular trafficking. A vast number of IDPs are also capable of liquid–liquid phase separation (LLPS), a driving force behind membrane=less organelle (MLO) formation.

The promiscuous nature of IDP interactions increases the chance for misfolding; for example, a significant number of neurodegenerative disease-linked proteins are IDPs, and their aggregation results in the amyloidal fibrils observed in patient neurons. Misregulation of IDPs also leads to their dysfunction, as mutations and post-translational modifications lead to altered molecular interactions that translate to cancer and other diseases.

This Special Issue includes papers contributing to the field of the function and dysfunction of IDPs.

Dr. Josephine Ferreon
Dr. Allan Chris M. Ferreon
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 submissions that pass pre-check are 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 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.

Related Special Issue

Published Papers (5 papers)

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Research

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22 pages, 4233 KiB  
Article
Does Generic Cyclic Kinase Insert Domain of Receptor Tyrosine Kinase KIT Clone Its Native Homologue?
by Julie Ledoux and Luba Tchertanov
Int. J. Mol. Sci. 2022, 23(21), 12898; https://doi.org/10.3390/ijms232112898 - 25 Oct 2022
Cited by 2 | Viewed by 1462
Abstract
Receptor tyrosine kinases (RTKs) are modular membrane proteins possessing both well-folded and disordered domains acting together in ligand-induced activation and regulation of post-transduction processes that tightly couple extracellular and cytoplasmic events. They ensure the fine-turning control of signal transmission by signal transduction. Deregulation [...] Read more.
Receptor tyrosine kinases (RTKs) are modular membrane proteins possessing both well-folded and disordered domains acting together in ligand-induced activation and regulation of post-transduction processes that tightly couple extracellular and cytoplasmic events. They ensure the fine-turning control of signal transmission by signal transduction. Deregulation of RTK KIT, including overexpression and gain of function mutations, has been detected in several human cancers. In this paper, we analysed by in silico techniques the Kinase Insert Domain (KID), a key platform of KIT transduction processes, as a generic macrocycle (KIDGC), a cleaved isolated polypeptide (KIDC), and a natively fused TKD domain (KIDD). We assumed that these KID species have similar structural and dynamic characteristics indicating the intrinsically disordered nature of this domain. This finding means that both polypeptides, cyclic KIDGC and linear KIDC, are valid models of KID integrated into the RTK KIT and will be helpful for further computational and empirical studies of post-transduction KIT events. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs) 2.0)
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12 pages, 2184 KiB  
Article
The Regulatory Roles of Intrinsically Disordered Linker in VRN1-DNA Phase Separation
by Qiaojing Huang, Yanyan Wang, Zhirong Liu and Luhua Lai
Int. J. Mol. Sci. 2022, 23(9), 4594; https://doi.org/10.3390/ijms23094594 - 21 Apr 2022
Cited by 2 | Viewed by 1671
Abstract
Biomacromolecules often form condensates to function in cells. VRN1 is a transcriptional repressor that plays a key role in plant vernalization. Containing two DNA-binding domains connected by an intrinsically disordered linker (IDL), VRN1 was shown to undergo liquid-like phase separation with DNA, and [...] Read more.
Biomacromolecules often form condensates to function in cells. VRN1 is a transcriptional repressor that plays a key role in plant vernalization. Containing two DNA-binding domains connected by an intrinsically disordered linker (IDL), VRN1 was shown to undergo liquid-like phase separation with DNA, and the length and charge pattern of IDL play major regulatory roles. However, the underlying mechanism remains elusive. Using a polymer chain model and lattice-based Monte-Carlo simulations, we comprehensively investigated how the IDL regulates VRN1 and DNA phase separation. Using a worm-like chain model, we showed that the IDL controls the binding affinity of VRN1 to DNA, by modulating the effective local concentration of the VRN1 DNA-binding domains. The predicted binding affinities, under different IDL lengths, were in good agreement with previously reported experimental results. Our simulation of the phase diagrams of the VRN1 variants with neutral IDLs and DNA revealed that the ability of phase separation first increased and then decreased, along with the increase in the linker length. The strongest phase separation ability was achieved when the linker length was between 40 and 80 residues long. Adding charged patches to the IDL resulted in robust phase separation that changed little with IDL length variations. Our study provides mechanism insights on how IDL regulates VRN1 and DNA phase separation, and why naturally occurring VRN1-like proteins evolve to contain the charge segregated IDL sequences, which may also shed light on the molecular mechanisms of other IDL-regulated phase separation processes in living cells. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs) 2.0)
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30 pages, 74296 KiB  
Article
Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein
by Julie Ledoux, Maxim Stolyarchuk, Enki Bachelier, Alain Trouvé and Luba Tchertanov
Int. J. Mol. Sci. 2022, 23(7), 3899; https://doi.org/10.3390/ijms23073899 - 31 Mar 2022
Cited by 3 | Viewed by 1726
Abstract
Human vitamin K epoxide reductase (hVKORC1) enzymatic activity requires an initial activation by a specific redox protein, a less studied step in the hVKORC1 vital cycle. Significant steric conditions must be met by enzymes, being that to adapt their configurations is mandatory for [...] Read more.
Human vitamin K epoxide reductase (hVKORC1) enzymatic activity requires an initial activation by a specific redox protein, a less studied step in the hVKORC1 vital cycle. Significant steric conditions must be met by enzymes, being that to adapt their configurations is mandatory for hVKORC1 activation. We studied, by molecular dynamics (MD) simulations, the folding and conformational plasticity of hVKORC1 in its inactive (fully oxidised) state using available structures, crystallographic and from de novo modelling. According to the obtained results, hVKORC1 is a modular protein composed of the stable transmembrane domain (TMD) and intrinsically disordered luminal (L) loop, possessing the great plasticity/adaptability required to perform various steps of the activation process. The docking (HADDOCK) of Protein Disulfide Isomerase (PDI) onto different hVKORC1 conformations clearly indicated that the most interpretable solutions were found on the target closed L-loop form, a prevalent conformation of hVKORC1’s oxidised state. We also suggest that the cleaved L-loop is an appropriate entity to study hVKORC1 recognition/activation by its redox protein. Additionally, the application of hVKORC1 (membrane protein) in aqueous solution is likely to prove to be very useful in practice in either in silico studies or in vitro experiments. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs) 2.0)
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Review

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17 pages, 1232 KiB  
Review
Aggregation of Disordered Proteins Associated with Neurodegeneration
by Phoebe S. Tsoi, My Diem Quan, Josephine C. Ferreon and Allan Chris M. Ferreon
Int. J. Mol. Sci. 2023, 24(4), 3380; https://doi.org/10.3390/ijms24043380 - 8 Feb 2023
Cited by 13 | Viewed by 3311
Abstract
Cellular deposition of protein aggregates, one of the hallmarks of neurodegeneration, disrupts cellular functions and leads to neuronal death. Mutations, posttranslational modifications, and truncations are common molecular underpinnings in the formation of aberrant protein conformations that seed aggregation. The major proteins involved in [...] Read more.
Cellular deposition of protein aggregates, one of the hallmarks of neurodegeneration, disrupts cellular functions and leads to neuronal death. Mutations, posttranslational modifications, and truncations are common molecular underpinnings in the formation of aberrant protein conformations that seed aggregation. The major proteins involved in neurodegeneration include amyloid beta (Aβ) and tau in Alzheimer’s disease, α-synuclein in Parkinson’s disease, and TAR DNA-binding protein (TDP-43) in amyotrophic lateral sclerosis (ALS). These proteins are described as intrinsically disordered and possess enhanced ability to partition into biomolecular condensates. In this review, we discuss the role of protein misfolding and aggregation in neurodegenerative diseases, specifically highlighting implications of changes to the primary/secondary (mutations, posttranslational modifications, and truncations) and the quaternary/supramolecular (oligomerization and condensation) structural landscapes for the four aforementioned proteins. Understanding these aggregation mechanisms provides insights into neurodegenerative diseases and their common underlying molecular pathology. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs) 2.0)
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30 pages, 1279 KiB  
Review
Intrinsically Disordered Proteins: An Overview
by Rakesh Trivedi and Hampapathalu Adimurthy Nagarajaram
Int. J. Mol. Sci. 2022, 23(22), 14050; https://doi.org/10.3390/ijms232214050 - 14 Nov 2022
Cited by 33 | Viewed by 7020
Abstract
Many proteins and protein segments cannot attain a single stable three-dimensional structure under physiological conditions; instead, they adopt multiple interconverting conformational states. Such intrinsically disordered proteins or protein segments are highly abundant across proteomes, and are involved in various effector functions. This review [...] Read more.
Many proteins and protein segments cannot attain a single stable three-dimensional structure under physiological conditions; instead, they adopt multiple interconverting conformational states. Such intrinsically disordered proteins or protein segments are highly abundant across proteomes, and are involved in various effector functions. This review focuses on different aspects of disordered proteins and disordered protein regions, which form the basis of the so-called “Disorder–function paradigm” of proteins. Additionally, various experimental approaches and computational tools used for characterizing disordered regions in proteins are discussed. Finally, the role of disordered proteins in diseases and their utility as potential drug targets are explored. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs) 2.0)
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