bims-indpro Biomed News
on Intrinsically disordered proteins
Issue of 2022‒05‒01
thirteen papers selected by
Sara Mingu
Johannes Gutenberg University
  1. The return of the rings: Evolutionary convergence of aromatic residues in the intrinsically disordered regions of RNA-binding proteins for liquid-liquid phase separation.
  2. Prediction of disordered regions in proteins with recurrent Neural Networks and protein dynamics.
  3. [Intrinsically disordered proteins (IDPs) and the impact on cell stress resistance].
  4. Phase separation driven by interchangeable properties in the intrinsically disordered regions of protein paralogs.
  5. Backbone and side chain resonance assignment of the intrinsically disordered human DBNDD1 protein.
  6. An enhancer sequence in the intrinsically disordered region of FtsZ promotes polymer-guided substrate processing by ClpXP protease.
  7. A robust preparation method for the amyloidogenic and intrinsically disordered amyloid-α (Aα) peptide.
  8. Design, Synthesis, and Biological Evaluation of Potent 20S Proteasome Activators for the Potential Treatment of α-Synucleinopathies.
  9. Integrative ensemble modeling of proteins and their complexes with distance distribution restraints.
  10. Interplay of Affinity and Surface Tethering in Protein Recognition.
  11. α-Synuclein phase separation and amyloid aggregation are modulated by C-terminal truncations.
  12. Tuning levels of low-complexity domain interactions to modulate endogenous oncogenic transcription.
  13. Unique seeding profiles and prion-like propagation of synucleinopathies are highly dependent on the host in human α-synuclein transgenic mice.
  1. Protein Sci. 2022 May;31(5): e4317
    The return of the rings: Evolutionary convergence of aromatic residues in the intrinsically disordered regions of RNA-binding proteins for liquid-liquid phase separation.
    Wen-Lin Ho, Jie-Rong Huang.
      Aromatic residues appeared relatively late in the evolution of protein sequences to stabilize the globular proteins' folding core and are less in the intrinsically disordered regions (IDRs). Recent advances in protein liquid-liquid phase separation (LLPS) studies have also shown that aromatic residues in IDRs often act as "stickers" to promote multivalent interactions in forming higher-order oligomers. To study how general these structure-promoting residues are in IDRs, we compared levels of sequence disorder in RNA binding proteins (RBPs), which are often found to undergo LLPS, and the human proteome. We found that aromatic residues appear more frequently than expected in the IDRs of RBPs and, through multiple sequence alignment analysis, those aromatic residues are often conserved among chordates. Using TDP-43, FUS, and some other well-studied LLPS proteins as examples, the conserved aromatic residues are important to their LLPS-related functions. These analyses suggest that aromatic residues may have contributed twice to evolution: stabilizing structured proteins and assembling biomolecular condensates.
    Keywords:  RNA-binding proteins; biomolecular condensates; intrinsically disordered proteins; liquid-liquid phase separation; membraneless organelle
    DOI:  https://doi.org/10.1002/pro.4317
  2. J Mol Biol. 2022 Apr 22. pii: S0022-2836(22)00159-0. [Epub ahead of print] 167579
    Prediction of disordered regions in proteins with recurrent Neural Networks and protein dynamics.
    Gabriele Orlando, Daniele Raimondi, Francesco Codice, Francesco Tabaro, Wim Vranken.
      The role of intrinsically disordered protein regions (IDRs) in cellular processes has become increas- ingly evident over the last years. These IDRs continue to challenge structural biology experiments be- cause they lack a well-defined conformation, and bioinformatics approaches that accurately delineate dis- ordered protein regions remain essential for their identification and further investigation. Typically, these predictors use the protein amino acid sequence, without taking into account likely sequence-dependent emergent properties, such as protein backbone dynamics. Here we present DisoMine, a method that predicts protein 'long disorder' with recurrent neural net- works from simple predictions of protein dynamics, secondary structure and early folding. The tool is fast and requires only a single sequence, making it applicable for large-scale screening, including poorly studied and orphan proteins. DisoMine is a top performer in its category and compares well to disorder prediction approaches using evolutionary information. DisoMine is freely available through an interactive webserver at https://bio2byte.be/disomine/.
    Keywords:  intrinsically disordered proteins; machine learning; neural networks; protein backbone dynamics; protein disorder prediction
    DOI:  https://doi.org/10.1016/j.jmb.2022.167579
  3. Sheng Wu Gong Cheng Xue Bao. 2022 Apr 25. 38(4): 1490-1505
    [Intrinsically disordered proteins (IDPs) and the impact on cell stress resistance].
    Ning Yan, Hongxing Li, Longhao Wu, Shuo Yang, Lujiang Hao, Xiaoming Bao.
      Intrinsically disordered proteins (IDPs) are proteins or protein regions that fail to get folded into definite three-dimensional structures but participate in various biological processes and perform specific functions. Defying the traditional protein "sequence-structure-function" paradigm, they enrich the protein "structure-function" diversity. Ubiquitous in organisms, they show extreme hydrophilicity, charged amino acids, and highly repetitive amino acid sequences, with simple arrangement. As a result, they feature highly variable binding affinities and high coordination, which facilitate their functions. IDPs play an important role in cell stress response, which can improve the tolerance to a variety of stresses, such as freezing, high salt, heat shock, and desiccation. In this study, we briefed the characteristics, classifications, and identification of IDPs, summarized the molecular mechanism in improving cell stress resistance, and described the potential applications.
    Keywords:  desiccation tolerance; freeze tolerance; heat shock; intrinsically disordered proteins; protein function; salt tolerance; stress response; structure prediction
    DOI:  https://doi.org/10.13345/j.cjb.210634
  4. Commun Biol. 2022 Apr 29. 5(1): 400
    Phase separation driven by interchangeable properties in the intrinsically disordered regions of protein paralogs.
    Shih-Hui Chiu, Wen-Lin Ho, Yung-Chen Sun, Jean-Cheng Kuo, Jie-Rong Huang.
      Paralogs, arising from gene duplications, increase the functional diversity of proteins. Protein functions in paralog families have been extensively studied, but little is known about the roles that intrinsically disordered regions (IDRs) play in their paralogs. Without a folded structure to restrain them, IDRs mutate more diversely along with evolution. However, how the diversity of IDRs in a paralog family affects their functions is unexplored. Using the RNA-binding protein Musashi family as an example, we applied multiple structural techniques and phylogenetic analysis to show how members in a paralog family have evolved their IDRs to different physicochemical properties but converge to the same function. In this example, the lower prion-like tendency of Musashi-1's IDRs, rather than Musashi-2's, is compensated by its higher α-helical propensity to assist their assembly. Our work suggests that, no matter how diverse they become, IDRs could evolve different traits to a converged function, such as liquid-liquid phase separation.
    DOI:  https://doi.org/10.1038/s42003-022-03354-4
  5. Biomol NMR Assign. 2022 Apr 26.
    Backbone and side chain resonance assignment of the intrinsically disordered human DBNDD1 protein.
    Christoph Wiedemann, Kingsley Benjamin Obika, Sandra Liebscher, Jan Jirschitzka, Oliver Ohlenschläger, Frank Bordusa.
      The dysbindin domain-containing protein 1 (DBNDD1) is a conserved protein among higher eukaryotes whose structure and function are poorly investigated so far. Here, we present the backbone and side chain nuclear magnetic resonance assignments for the human DBNDD1 protein. Our chemical-shift based secondary structure analysis reveals the human DBNDD1 as an intrinsically disordered protein.
    Keywords:  Backbone and side chain nuclear magnetic resonance assignments; Chemical shifts; Dysbindin domain-containing protein 1 (DBNDD1); Dystrobrevin-binding protein; Intrinsically disordered protein (IDP); Solution NMR; Solution state nuclear magnetic resonance
    DOI:  https://doi.org/10.1007/s12104-022-10086-3
  6. Protein Sci. 2022 May;31(5): e4306
    An enhancer sequence in the intrinsically disordered region of FtsZ promotes polymer-guided substrate processing by ClpXP protease.
    Marissa G Viola, Theodora Myrto Perdikari, Catherine E Trebino, Negar Rahmani, Kaylee L Mathews, Carolina Mejia Pena, Xien Yu Chua, Botai Xuan, Christopher J LaBreck, Nicolas L Fawzi, Jodi L Camberg.
      The essential bacterial division protein in Escherichia coli, FtsZ, assembles into the FtsZ-ring at midcell and recruits other proteins to the division site to promote septation. A region of the FtsZ amino acid sequence that links the conserved polymerization domain to a C-terminal protein interaction site was predicted to be intrinsically disordered and has been implicated in modulating spacing and architectural arrangements of FtsZ filaments. While the majority of cell division proteins that directly bind to FtsZ engage either the polymerization domain or the C-terminal interaction site, ClpX, the recognition and unfolding component of the bacterial ClpXP proteasome, has a secondary interaction with the predicted intrinsically disordered region (IDR) of FtsZ when FtsZ is polymerized. Here, we use NMR spectroscopy and reconstituted degradation reactions in vitro to demonstrate that this linker region is indeed disordered in solution and, further, that amino acids in the IDR of FtsZ enhance the degradation in polymer-guided interactions.
    Keywords:  cytokinesis; disorder; division; proteolysis; turnover
    DOI:  https://doi.org/10.1002/pro.4306
  7. J Pept Sci. 2022 Apr 28. e3414
    A robust preparation method for the amyloidogenic and intrinsically disordered amyloid-α (Aα) peptide.
    Ariel J Kuhn, Jevgenij A Raskatov.
      Recent findings suggest that amyloid-β may not the only peptidic culprit for the cognitive decline observed in patients with Alzheimer's disease. A C-terminal fragment of Aβ, amyloid-α (Aα), also known as p3, has been shown to form amyloidogenic oligomers and fibrils more rapidly than Aβ. However, the insolubility and aggregation propensity of this 24-26-residue peptide makes it exceptionally difficult to produce, purify, and subsequently study. This paper reports a reproducible, multi-step method for the purification and pre-treatment of Aα and related analogues, yielding 95-99% pure peptides. We anticipate that the methods described herein will permit previously inaccessible biophysical and biological experiments that may be critical to understanding the role of this too long overlooked peptide in AD disease pathology.
    Keywords:  aggregation; amyloid; intrinsically disordered protein; peptide; purification
    DOI:  https://doi.org/10.1002/psc.3414
  8. J Med Chem. 2022 Apr 27.
    Design, Synthesis, and Biological Evaluation of Potent 20S Proteasome Activators for the Potential Treatment of α-Synucleinopathies.
    Sophia D Staerz, Corey L Jones, Jetze J Tepe.
      While neurodegenerative diseases affect millions of patients worldwide, there are insufficient available therapeutics to halt or slow down the progression of these diseases. A key pathological feature of several neurodegenerative diseases is the oligomerization and aggregation of specific intrinsically disordered proteins (IDPs) creating neuronal deposits, such as Lewy bodies in Parkinson's disease. Clearance of these pathogenic, aggregation-prone IDPs is mediated by the 20S isoform of the human proteasome. Thus, enhancing the 20S proteasome-mediated proteolysis could be a very useful therapeutic pathway to prevent neurotoxicity. Here, we report the successful development of sub-microM 20S proteasome activators based on a phenothiazine scaffold. This class of compounds prevented the accumulation of pathologically relevant IDPs, such as the pathogenic A53T mutated α-synuclein, in vitro and in mammalian cell lines.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c02158
  9. Methods Enzymol. 2022 ;pii: S0076-6879(22)00041-6. [Epub ahead of print]666 145-169
    Integrative ensemble modeling of proteins and their complexes with distance distribution restraints.
    Gunnar Jeschke, Laura Esteban-Hofer.
      Many proteins and protein complexes exhibit regions that are intrinsically disordered. Whereas an arsenal of techniques exists to characterize structured proteins or protein regions, characterization of the vast conformational space occupied by intrinsically disordered regions remains a challenging task due the ensemble-averaging nature of many techniques that provide mean value restraints. More representative information can be gained in the form of distribution restraints, such as EPR-derived distance distributions. Previously we developed the ensemble modeling tool MMM, where we partition the macromolecule into structured and unstructured domains and utilize an integrative structural approach with a focus on EPR-derived distance restraints. Here we present the successor program of MMM: MMMx. All the modeling functionality was ported to MMMx and is now accessed by a uniform script format, allowing to combine the different modules at will to modeling pipelines. During the conception of MMMx many of the tools were improved or updated. We discuss the general functionality of MMMx and its modules, and illustrate some of the modeling tools by application examples.
    Keywords:  Distance distributions; Electron paramagnetic resonance; Ensemble structures; Integrative structural biology; Modeling; NMR; Small-angle scattering
    DOI:  https://doi.org/10.1016/bs.mie.2022.02.010
  10. J Phys Chem Lett. 2022 Apr 29. 4021-4028
    Interplay of Affinity and Surface Tethering in Protein Recognition.
    Ali Imran, Brandon S Moyer, Aaron J Wolfe, Michael S Cosgrove, Dmitrii E Makarov, Liviu Movileanu.
      Surface-tethered ligand-receptor complexes are key components in biological signaling and adhesion. They also find increasing utility in single-molecule assays and biotechnological applications. Here, we study the real-time binding kinetics between various surface-immobilized peptide ligands and their unrestrained receptors. A long peptide tether increases the association of ligand-receptor complexes, experimentally proving the fly casting mechanism where the disorder accelerates protein recognition. On the other hand, a short peptide tether enhances the complex dissociation. Notably, the rate constants measured for the same receptor, but under different spatial constraints, are strongly correlated to one another. Furthermore, this correlation can be used to predict how surface tethering on a ligand-receptor complex alters its binding kinetics. Our results have immediate implications in the broad areas of biomolecular recognition, intrinsically disordered proteins, and biosensor technology.
    DOI:  https://doi.org/10.1021/acs.jpclett.2c00621
  11. FEBS Lett. 2022 Apr 29.
    α-Synuclein phase separation and amyloid aggregation are modulated by C-terminal truncations.
    Shuai Huang, Xiaoli Mo, Jieyi Wang, Xinyi Ye, Haijia Yu, Yinghui Liu.
      The aggregation of α-synuclein (α-Syn) is a key pathological hallmark of Parkinson's disease (PD). α-Syn undergoes liquid-liquid phase separation (LLPS) to drive amyloid aggregation. How the LLPS of α-Syn is regulated remains largely unknown. Here, we discovered that the C-terminal region modulates α-Syn phase separation through electrostatic interactions. The wild-type (WT) and PD disease-related truncated α-Syn can co-exist in the condensates. The truncated α-Syn could dramatically promote WT α-Syn phase separation. Further studies demonstrated that the truncated α-Syn accelerated WT α-Syn turning to amyloid aggregates by modulation of phase separation. Together, our findings disclose the role of the C-terminal domain in the LLPS of α-Syn and pave the path for understanding the mechanism of truncated α-Syn in PD pathology.
    Keywords:  C-terminal truncation; aggregation; droplet; liquid-liquid phase separation (LLPS); α-synuclein
    DOI:  https://doi.org/10.1002/1873-3468.14361
  12. Mol Cell. 2022 Apr 19. pii: S1097-2765(22)00318-5. [Epub ahead of print]
    Tuning levels of low-complexity domain interactions to modulate endogenous oncogenic transcription.
    Shasha Chong, Thomas G W Graham, Claire Dugast-Darzacq, Gina M Dailey, Xavier Darzacq, Robert Tjian.
      Gene activation by mammalian transcription factors (TFs) requires multivalent interactions of their low-complexity domains (LCDs), but how such interactions regulate transcription remains unclear. It has been proposed that extensive LCD-LCD interactions culminating in liquid-liquid phase separation (LLPS) of TFs is the dominant mechanism underlying transactivation. Here, we investigated how tuning the amount and localization of LCD-LCD interactions in vivo affects transcription of endogenous human genes. Quantitative single-cell and single-molecule imaging reveals that the oncogenic TF EWS::FLI1 requires a narrow optimum of LCD-LCD interactions to activate its target genes associated with GGAA microsatellites. Increasing LCD-LCD interactions toward putative LLPS represses transcription of these genes in patient-derived cells. Likewise, ectopically creating LCD-LCD interactions to sequester EWS::FLI1 into a well-documented LLPS compartment, the nucleolus, inhibits EWS::FLI1-driven transcription and oncogenic transformation. Our findings show how altering the balance of LCD-LCD interactions can influence transcriptional regulation and suggest a potential therapeutic strategy for targeting disease-causing TFs.
    Keywords:  EWS::FLI1; Ewing sarcoma; intrinsically disordered regions; liquid-liquid phase separation; low-complexity domains; multivalent interactions; nucleolus; single-cell and single-molecule imaging; transcription factor; transcriptional control
    DOI:  https://doi.org/10.1016/j.molcel.2022.04.007
  13. Acta Neuropathol. 2022 Apr 30.
    Unique seeding profiles and prion-like propagation of synucleinopathies are highly dependent on the host in human α-synuclein transgenic mice.
    Grace M Lloyd, Zachary A Sorrentino, Stephan Quintin, Kimberly-Marie M Gorion, Brach M Bell, Giavanna Paterno, Brooke Long, Stefan Prokop, Benoit I Giasson.
      α-synuclein (αSyn) is an intrinsically disordered protein which can undergo structural transformations, resulting in the formation of stable, insoluble fibrils. αSyn amyloid-type nucleation can be induced by misfolded 'seeds' serving as a conformational template, tantamount to the prion-like mechanism. Accumulation of αSyn inclusions is a key feature of dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), and are found as additional pathology in Alzheimer's disease (AD) such as AD with amygdala predominant Lewy bodies (AD/ALB). While these disorders accumulate the same pathological protein, they exhibit heterogeneity in clinical and histological features; however, the mechanism(s) underlying this variability remains elusive. Accruing data from human autopsy studies, animal inoculation modeling, and in vitro characterization experiments, have lent credence to the hypothesis that conformational polymorphism of the αSyn amyloid-type fibril structure results in distinct "strains" with categorical infectivity traits. Herein, we directly compare the seeding abilities and outcome of human brain lysates from these diseases, as well as recombinant preformed human αSyn fibrils by the intracerebral inoculation of transgenic mice overexpressing either human wild-type αSyn or human αSyn with the familial A53T mutation. Our study has revealed that the initiating inoculum heavily dictates the phenotypic and pathological course of disease. Interestingly, we have also established relevant host-dependent distinctions between propagation profiles, including burden and spread of inclusion pathology throughout the neuroaxis, as well as severity of neurological symptoms. These findings provide compelling evidence supporting the hypothesis that diverse prion-type conformers may explain the variability seen in synucleinopathies.
    Keywords:  Alzheimer’s disease with amygdala predominant Lewy bodies; Amyloid; Dementia with Lewy bodies; Multiple system atrophy; Prion; Strains; Synucleinopathy; α-synuclein
    DOI:  https://doi.org/10.1007/s00401-022-02425-4
This page is being maintained by Thomas Krichel. It was last updated on 2022‒05‒27 at 10:34:59.