Special Issue "Protein Intrinsic Disorder: Role in Signaling, Regulation and Membrane-Less Organelle Formation"

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 30 June 2021.

Special Issue Editors

Dr. Nathalie Sibille
E-Mail Website
Guest Editor
Centre de Biochimie Structurale (CBS), CNRS, INSERM, University of Montpellier, Montpellier, France
Interests: intrinsically disordered proteins (IDPs); post-translational modifications (PTMs); signaling; nuclear magnetic resonance (NMR); small-angle X-ray scattering (SAXS)
Dr. Sonia Longhi
E-Mail Website
Guest Editor
Architecture and Function of Biological Macromolecules (AFMB), UMR 7257 CNRS & Aix-Marseille University, 13288 Marseille, France
Interests: intrinsically disordered proteins; folding copuled to binding; protein-protein interactions; structural transitions; paramyxoviruses
Special Issues and Collections in MDPI journals
Dr. Carine Van Heijenoort
E-Mail Website
Guest Editor
ICSN-CNRS, Université Paris-Saclay, Gif-sur-Yvette, France
Interests: structural biology; NMR; intrinsically disordered proteins; relation structure; dynamics and function of proteins; protein-protein interactions; protein-ligand interaction

Special Issue Information

Dear Colleagues,

Intrinsically disordered proteins (IDPs) are fascinating multifaceted proteins. Their discovery dates back to the mid-1990s, and it is now well established that IDPs are very common in the protein realm. They are particularly abundant in the proteome of eukaryotes, with this prevalence being tied to the higher complexity of the latter compared to prokaryotes. The lack of stable secondary and tertiary structure that typifies these proteins and that is encoded by their amino acid sequence makes these proteins very elusive; thus, IDPs and their complexes are very difficult to characterize at the structural level due to their inherent flexibility. Although IDPs lack a fixed 3D structure, they can feature transiently populated secondary structure elements, which are often conserved and linked to function. In particular, these elements often serve as binding sites for partners and attenuate the entropic cost of the disorder-to-order transition triggered by binding to the partner. Many IDPs conserve a considerable extent of residual disorder upon binding to a partner, leading to so-called “fuzzy complexes”. By tuning the extent of preconfiguration and/or of fuzziness, IDPs can finely tune their affinity towards multiple partners. They can establish interactions ranging from low to high affinity, while conserving specificity in all cases. All these features are also modified by frequent post-translational modifications due to their high flexibility and accessibility. As such, they are the target of more than 300 PTMs that ultimately modulate their structural features and their ability to interact with partners. Thanks to these peculiar biophysical and biochemical features, IDPs are widely involved in signaling and regulation. Their action is also highly dependent on their expression level and local concentration in the cell. In the last five years, a growing number of studies has thus addressed the ability of IDPs to undergo liquid–liquid phase separation (LLPS), a phenomenon that underlies the formation of membrane-less organelles (MLOs). As a consequence, the deregulation of processes implying IDPs is at the origin of a multitude of diseases such as cancer, neurodegeneration, cardiovascular diseases, and diabetes. In order to better understand the mechanisms behind these diseases, it is necessary to decipher their structural bases. This Special Issue on “Protein Intrinsic Disorder: Role in Signaling, Regulation and Membrane-Less Organelle Formation” aims at further deepening our understanding of how the physicochemical properties of IDPs enable them to play a crucial role in the regulation of many critical biological processes.

Dr. Nathalie Sibille
Dr. Sonia Longhi
Dr. Carine Van Heijenoort
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. 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 2000 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

  • intrinsically disordered proteins (IDPs)
  • signaling
  • regulation
  • post-translational modification (PTM)
  • membrane-less organelle formation (MLOs)
  • liquid–liquid phase separation (LLPS)
  • nuclear magnetic resonance (NMR)
  • integrative structural biology

Published Papers (2 papers)

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Research

Open AccessArticle
Flexibility of Oxidized and Reduced States of the Chloroplast Regulatory Protein CP12 in Isolation and in Cell Extracts
Biomolecules 2021, 11(5), 701; https://doi.org/10.3390/biom11050701 - 08 May 2021
Viewed by 254
Abstract
In the chloroplast, Calvin–Benson–Bassham enzymes are active in the reducing environment created in the light by electrons from the photosystems. In the dark, these enzymes are inhibited, mainly caused by oxidation of key regulatory cysteine residues. CP12 is a small protein that plays [...] Read more.
In the chloroplast, Calvin–Benson–Bassham enzymes are active in the reducing environment created in the light by electrons from the photosystems. In the dark, these enzymes are inhibited, mainly caused by oxidation of key regulatory cysteine residues. CP12 is a small protein that plays a role in this regulation with four cysteine residues that undergo a redox transition. Using amide-proton exchange with solvent, measured by nuclear magnetic resonance (NMR) and mass-spectrometry, we confirmed that reduced CP12 is intrinsically disordered. Using real-time NMR, we showed that the oxidation of the two disulfide bridges is simultaneous. In oxidized CP12, the C23–C31 pair is in a region that undergoes a conformational exchange in the NMR-intermediate timescale. The C66–C75 pair is in the C-terminus that folds into a stable helical turn. We confirmed that these structural states exist in a physiologically relevant environment: a cell extract from Chlamydomonas reinhardtii. Consistent with these structural equilibria, the reduction is slower for the C66–C75 pair than for the C23–C31 pair. The redox mid-potentials for the two cysteine pairs differ and are similar to those found for glyceraldehyde 3-phosphate dehydrogenase and phosphoribulokinase, consistent with the regulatory role of CP12. Full article
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Open AccessArticle
Adenoviral E1A Exploits Flexibility and Disorder to Target Cellular Proteins
Biomolecules 2020, 10(11), 1541; https://doi.org/10.3390/biom10111541 - 11 Nov 2020
Cited by 2 | Viewed by 649
Abstract
Direct interaction between intrinsically disordered proteins (IDPs) is often difficult to characterize hampering the elucidation of their binding mechanism. Particularly challenging is the study of fuzzy complexes, in which the intrinsically disordered proteins or regions retain conformational freedom within the assembly. To date, [...] Read more.
Direct interaction between intrinsically disordered proteins (IDPs) is often difficult to characterize hampering the elucidation of their binding mechanism. Particularly challenging is the study of fuzzy complexes, in which the intrinsically disordered proteins or regions retain conformational freedom within the assembly. To date, nuclear magnetic resonance spectroscopy has proven to be one of the most powerful techniques to characterize at the atomic level intrinsically disordered proteins and their interactions, including those cases where the formed complexes are highly dynamic. Here, we present the characterization of the interaction between a viral protein, the Early region 1A protein from Adenovirus (E1A), and a disordered region of the human CREB-binding protein, namely the fourth intrinsically disordered linker CBP-ID4. E1A was widely studied as a prototypical viral oncogene. Its interaction with two folded domains of CBP was mapped, providing hints for understanding some functional aspects of the interaction with this transcriptional coactivator. However, the role of the flexible linker connecting these two globular domains of CBP in this interaction was never explored before. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Intrinsic disorder in BRCA2 facilitates tight regulation of multiple conserved binding events
Authors: Julien Manon; Petitalot Ambre; Ghouil Rania; Sandrine Caputo; Carreira Aura; Zinn-Justin Sophie
Affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette Cedex, France Department of Biology, École Normale Supérieure, 94230 Cachan, France Service de génétique, unité de génétique constitutionnelle, Institut Curie, 26 rue d'Ulm, Paris, France Paris Sciences Lettres Research University, Paris, France Institut Curie, PSL Research University, CNRS, UMR3348, F-91405, Orsay, France Paris Sud University, Paris-Saclay University CNRS, UMR3348, F-91405 Orsay, France
Abstract: The maintenance of genome integrity in the cell is an essential process for the accurate transmission of the genetic material. BRCA2 participates in this process at several levels, including DNA repair by homologous recombination, protection of stalled replication forks and cell division. These activities are regulated and coordinated via cell-cycle dependent modifications. Mutations in BRCA2 cause genome instability and are associated with breast and ovarian cancers. BRCA2 is a very large protein of 3418 amino acids. Most well-characterized mutations causing a strong predisposition to cancer are located in the C-terminal 700 amino acids DNA binding domain of BRCA2. The rest of the BRCA2 protein is predicted to be disordered. Interactions involving intrinsically disordered regions (IDRs) remain difficult to identify both using bioinformatics tools and performing experimental assays. Yet, the lack of well-structured binding sites provides unique functional opportunities for BRCA2 to bind to a large set of partners in a tightly regulated manner. We here summarize the predictive and experimental arguments that support the presence of disorder in BRCA2. We describe how BRCA2 IDRs mediate self-assembly and binding to partners during DNA double-strand break repair, mitosis and meiosis. We highlight how phosphorylation by cell-cycle and DNA repair kinases regulates these interactions.

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