bims-indpro Biomed News
on Intrinsically disordered proteins
Issue of 2022–02–06
fourteen papers selected by
Sara Mingu, Johannes Gutenberg University
  1. Crowding-induced phase separation of nuclear transport receptors in FG nucleoporin assemblies.
  2. Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation.
  3. Directed mutational scanning reveals a balance between acidic and hydrophobic residues in strong human activation domains.
  4. Fusion proteins drive cancer through phase separation.
  5. SARS-CoV-2 variants preferentially emerge at intrinsically disordered protein sites helping immune evasion.
  6. Databases for intrinsically disordered proteins.
  7. Rules of Physical Mathematics Govern Intrinsically Disordered Proteins.
  8. DisEnrich: Database of Enriched Regions in Human Dark Proteome.
  9. Mapping Critical Residues in ATG11's Coiled-Coil 2 Domain that Block Multiple Interactions and Disrupt Selective Autophagy.
  10. RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins.
  11. Interactions of intrinsically disordered proteins with the unconventional chaperone human serum albumin: From mechanisms of amyloid inhibition to therapeutic opportunities.
  12. Deep structural insights into RNA-binding disordered protein regions.
  13. Backbone NMR resonance assignment of the intrinsically disordered UBact protein from Nitrospira nitrosa.
  14. Solution NMR backbone assignments of disordered Olduvai protein domain CON1 employing Hα-detected experiments.
  1. Elife. 2022 Jan 31. pii: e72627. [Epub ahead of print]11
    Crowding-induced phase separation of nuclear transport receptors in FG nucleoporin assemblies.
    Luke K Davis, Ian J Ford, Bart W Hoogenboom.
      The rapid (< 1 ms) transport of biological material to and from the cell nucleus is regulated by the nuclear pore complex (NPC). At the core of the NPC is a permeability barrier consisting of intrinsically disordered Phe-Gly (FG) nucleoporins (FG Nups). Various types of nuclear transport receptors (NTRs) facilitate transport by partitioning in the FG Nup assembly, overcoming the barrier by their affinity to the FG Nups, and comprise a significant fraction of proteins in the NPC barrier. In previous work Zahn et al. (2016), we revealed a universal physical behaviour in the experimentally observed binding of two well-characterized NTRs, NTF2 and the larger Importin-β, to different planar assemblies of FG Nups, with the binding behaviour defined by negative cooperativity. This was further validated by a minimal physical model that treated the FG Nups as flexible homopolymers and the NTRs as uniformly cohesive spheres. Here, we build upon our original study by first parametrizing our model to experimental data, and next predicting the effects of crowding by different types of NTRs. We show how varying the amounts of one type of NTR modulates how the other NTR penetrates the FG Nup assembly. Notably, at similar and physiologically relevant NTR concentrations, our model predicts demixed phases of NTF2 and Imp-β within the FG Nup assembly. The functional implication of NTR phase separation is that NPCs may sustain separate transport pathways that are determined by inter-NTR competition.
    Keywords:  physics of living systems
    DOI:  https://doi.org/10.7554/eLife.72627
  2. EMBO J. 2022 Feb 03. e108443
    Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation.
    Lara A Gruijs da Silva, Francesca Simonetti, Saskia Hutten, Henrick Riemenschneider, Erin L Sternburg, Lisa M Pietrek, Jakob Gebel, Volker Dötsch, Dieter Edbauer, Gerhard Hummer, Lukas S Stelzl, Dorothee Dormann.
      Post-translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA-binding protein TAR DNA-binding protein (TDP-43), is hyperphosphorylated in disease on several C-terminal serine residues, a process generally believed to promote TDP-43 aggregation. Here, we however find that Casein kinase 1δ-mediated TDP-43 hyperphosphorylation or C-terminal phosphomimetic mutations reduce TDP-43 phase separation and aggregation, and instead render TDP-43 condensates more liquid-like and dynamic. Multi-scale molecular dynamics simulations reveal reduced homotypic interactions of TDP-43 low-complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP-43, but suppress accumulation of TDP-43 in membrane-less organelles and promote its solubility in neurons. We speculate that TDP-43 hyperphosphorylation may be a protective cellular response to counteract TDP-43 aggregation.
    Keywords:  RNA-binding protein; TDP-43; neurodegeneration; phase separation; phosphorylation
    DOI:  https://doi.org/10.15252/embj.2021108443
  3. Cell Syst. 2022 Jan 28. pii: S2405-4712(22)00002-3. [Epub ahead of print]
    Directed mutational scanning reveals a balance between acidic and hydrophobic residues in strong human activation domains.
    Max V Staller, Eddie Ramirez, Sanjana R Kotha, Alex S Holehouse, Rohit V Pappu, Barak A Cohen.
      Acidic activation domains are intrinsically disordered regions of the transcription factors that bind coactivators. The intrinsic disorder and low evolutionary conservation of activation domains have made it difficult to identify the sequence features that control activity. To address this problem, we designed thousands of variants in seven acidic activation domains and measured their activities with a high-throughput assay in human cell culture. We found that strong activation domain activity requires a balance between the number of acidic residues and aromatic and leucine residues. These findings motivated a predictor of acidic activation domains that scans the human proteome for clusters of aromatic and leucine residues embedded in regions of high acidity. This predictor identifies known activation domains and accurately predicts previously unidentified ones. Our results support a flexible acidic exposure model of activation domains in which the acidic residues solubilize hydrophobic motifs so that they can interact with coactivators. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  activation domain; all-atom simulations; deep mutational scanning; genomic method development; high-throughput mutagenesis; intrinsically disordered protein; intrinsically disordered region; transcription factor
    DOI:  https://doi.org/10.1016/j.cels.2022.01.002
  4. Nat Cancer. 2021 Dec;2(12): 1285
    Fusion proteins drive cancer through phase separation.
    Ioanna Pavlaki.
      
    DOI:  https://doi.org/10.1038/s43018-021-00295-5
  5. FEBS J. 2022 Feb 02.
    SARS-CoV-2 variants preferentially emerge at intrinsically disordered protein sites helping immune evasion.
    Federica Quaglia, Edoardo Salladini, Marco Carraro, Giovanni Minervini, Silvio C E Tosatto, Philippe Le Mercier.
      The SARS-CoV-2 pandemic is maintained by the emergence of successive variants, highlighting the flexibility of the protein sequences of the virus. We show that experimentally determined intrinsically disordered regions (IDRs) are abundant in the SARS-CoV-2 viral proteins, making up to 28% of disorder content for the S1 subunit of spike and up to 51% for the nucleoprotein, with the vast majority of mutations occurring in the 13 major variants mapped to these IDRs. Strikingly, antigenic sites are enriched in IDRs, in the receptor-binding domain (RBD) and in the N-terminal domain (NTD), suggesting a key role of structural flexibility in the antigenicity of the SARS-CoV-2 protein surface. Mutations occurring in the S1 subunit and nucleoprotein (N) IDRs are critical for immune evasion and antibody escape, suggesting potential additional implications for vaccines and monoclonal therapeutic strategies. Overall, this suggests the presence of variable regions on S1 and N protein surfaces, which confer sequence and antigenic flexibility to the virus without altering its protein functions.
    Keywords:  DisProt; IDPs; SARS-CoV-2; ViralZone; biocuration; immune escape; intrinsically disordered proteins; mutations; variants
    DOI:  https://doi.org/10.1111/febs.16379
  6. Acta Crystallogr D Struct Biol. 2022 Feb 01. 78(Pt 2): 144-151
    Databases for intrinsically disordered proteins.
    Damiano Piovesan, Alexander Miguel Monzon, Federica Quaglia, Silvio C E Tosatto.
      Intrinsically disordered regions (IDRs) lacking a fixed three-dimensional protein structure are widespread and play a central role in cell regulation. Only a small fraction of IDRs have been functionally characterized, with heterogeneous experimental evidence that is largely buried in the literature. Predictions of IDRs are still difficult to estimate and are poorly characterized. Here, an overview of the publicly available knowledge about IDRs is reported, including manually curated resources, deposition databases and prediction repositories. The types, scopes and availability of the various resources are analyzed, and their complementarity and overlap are highlighted. The volume of information included and the relevance to the field of structural biology are compared.
    Keywords:  databases; flexible proteins; intrinsically disordered proteins; protein ensembles
    DOI:  https://doi.org/10.1107/S2059798321012109
  7. Annu Rev Biophys. 2022 Feb 04.
    Rules of Physical Mathematics Govern Intrinsically Disordered Proteins.
    Kingshuk Ghosh, Jonathan Huihui, Michael Phillips, Austin Haider.
      In stark contrast to foldable proteins with a unique folded state, intrinsically disordered proteins and regions (IDPs) persist in perpetually disordered ensembles. Yet an IDP ensemble has conformational features-even when averaged-that are specific to its sequence. In fact, subtle changes in an IDP sequence can modulate its conformational features and its function. Recent advances in theoretical physics reveal a set of elegant mathematical expressions that describe the intricate relationships among IDP sequences, their ensemble conformations, and the regulation of their biological functions. These equations also describe the molecular properties of IDP sequences that predict similarities and dissimilarities in their functions and facilitate classification of sequences by function, an unmet challenge to traditional bioinformatics. These physical sequence-patterning metrics offer a promising new avenue for advancing synthetic biology at a time when multiple novel functional modes mediated by IDPs are emerging. Expected final online publication date for the Annual Review of Biophysics, Volume 51 is May 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biophys-120221-095357
  8. Bioinformatics. 2022 Jan 30. pii: btac051. [Epub ahead of print]
    DisEnrich: Database of Enriched Regions in Human Dark Proteome.
    Kirill E Medvedev, Jimin Pei, Nick V Grishin.
       MOTIVATION: Intrinsically disordered proteins (IDPs) are involved in numerous processes crucial for living organisms. Bias in amino acid composition of these proteins determines their unique biophysical and functional features. Distinct intrinsically disordered regions (IDRs) with compositional bias play different important roles in various biological processes. IDRs enriched in particular amino acids in human proteome have not been described consistently.
    RESULTS: We developed DisEnrich-the database of human proteome IDRs that are significantly enriched in particular amino acids. Each human protein is described using gene ontology (GO) function terms, disorder prediction for the full-length sequence using three methods, enriched IDR composition and ranks of human proteins with similar enriched IDRs. Distribution analysis of enriched IDRs among broad functional categories revealed significant overrepresentation of R- and Y-enriched IDRs in metabolic and enzymatic activities and F-enriched IDRs in transport. 75% of functional categories contain IDPs with IDRs significantly enriched in hydrophobic residues that are important for protein-protein interactions.
    AVAILABILITY: The database is available at http://prodata.swmed.edu/DisEnrichDB/.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btac051
  9. Front Cell Dev Biol. 2021 ;9 775364
    Mapping Critical Residues in ATG11's Coiled-Coil 2 Domain that Block Multiple Interactions and Disrupt Selective Autophagy.
    Mitchell D Meyer, Jasmine Winzeler, Sophia M Taylor, Alex Kilgore, Kimberly Edicha, Chase Chitwood, Zachary Spearin, S K Nadia Rahman Silvia, Ronith Chakraborty, Jesse E Smith, Bridget Kennedy, Carson Zois, Hayley Cawthon, Mukiri Gilruth, Steven K Backues.
      Selective autophagy is a conserved subcellular process that maintains the health of eukaryotic cells by targeting damaged or toxic cytoplasmic components to the vacuole/lysosome for degradation. A key player in the initiation of selective autophagy in S. Cerevisiae (baker's yeast) is a large adapter protein called Atg11. Atg11 has multiple predicted coiled-coil domains and intrinsically disordered regions, is known to dimerize, and binds and organizes other essential components of the autophagosome formation machinery, including Atg1 and Atg9. We performed systematic directed mutagenesis on the coiled-coil 2 domain of Atg11 in order to map which residues were required for its structure and function. Using yeast-2-hybrid and coimmunoprecipitation, we found only three residues to be critical: I562, Y565, and I569. Mutation of any of these, but especially Y565, could interfere with Atg11 dimerization and block its interaction with Atg1 and Atg9, thereby inactivating selective autophagy.
    Keywords:  Atg1; Atg11; Atg19; Atg9; coimmunoprecipitation; directed mutagenesis; selective autophagy; yeast-2-hybrid
    DOI:  https://doi.org/10.3389/fcell.2021.775364
  10. PLoS Comput Biol. 2022 Feb 02. 18(2): e1009810
    RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins.
    Ignacio Sanchez-Burgos, Jorge R Espinosa, Jerelle A Joseph, Rosana Collepardo-Guevara.
      Biomolecular condensates formed via liquid-liquid phase separation (LLPS) play a crucial role in the spatiotemporal organization of the cell material. Nucleic acids can act as critical modulators in the stability of these protein condensates. Here, we present a multiscale computational strategy, exploiting the advantages of both a sequence-dependent coarse-grained representation of proteins and a minimal coarse-grained model that describes proteins as patchy colloids, to unveil the role of RNA length in regulating the stability of RNA-binding protein (RBP) condensates. We find that for a constant nucleotide/protein ratio at which phase separation is enhanced, the protein fused in sarcoma (FUS), which can phase separate on its own-i.e., via homotypic interactions-only exhibits a mild dependency on the RNA strand length. In contrast, the 25-repeat proline-arginine peptide (PR25), which does not undergo LLPS on its own at physiological conditions but instead exhibits complex coacervation with RNA-i.e., via heterotypic interactions-shows a strong dependence on the length of the RNA strands. Our minimal patchy particle simulations, where we recapitulate the modulation of homotypic protein LLPS and complex coacervation by RNA length, suggest that the strikingly different effect of RNA length on homotypic LLPS versus complex coacervation is general. Phase separation is RNA-length dependent as long as the relative contribution of heterotypic interactions sustaining LLPS is comparable or higher than that stemming from protein homotypic interactions. Taken together, our results contribute to illuminate the intricate physicochemical mechanisms that influence the stability of RBP condensates through RNA inclusion.
    DOI:  https://doi.org/10.1371/journal.pcbi.1009810
  11. Biophys Chem. 2022 Mar;pii: S0301-4622(21)00226-X. [Epub ahead of print]282 106743
    Interactions of intrinsically disordered proteins with the unconventional chaperone human serum albumin: From mechanisms of amyloid inhibition to therapeutic opportunities.
    Karla Martinez Pomier, Rashik Ahmed, Giuseppe Melacini.
      Human Serum Albumin (HSA), the most abundant protein in plasma, serves a diverse repertoire of biological functions including regulation of oncotic pressure and redox potential, transport of serum solutes, but also chaperoning of misfolded proteins. Here we review how HSA interacts with a wide spectrum of client proteins including intrinsically disordered proteins (IDPs) such as Aβ, the islet amyloid peptide (IAPP), alpha synuclein and stressed globular proteins such as insulin. The comparative analysis of the HSA chaperone - client interactions reveals that the amyloid-inhibitory function of HSA arises from at least four emerging mechanisms. Two mechanisms (the monomer stabilizer model and the monomer competitor model) involve the direct binding of HSA to either IDP monomers or oligomers, while other mechanisms (metal chelation and membrane protection) rely on the indirect modulation by HSA of other factors that drive IDP aggregation. While HSA is not the only extracellular chaperone, given its abundance, HSA is likely to account for a significant fraction of the chaperoning effects in plasma, thus opening new therapeutic opportunities in the context of the peripheral sink hypothesis.
    Keywords:  Amyloid; Amyloid inhibition; Chaperone; Human serum albumin; Intrinsically disordered proteins; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.bpc.2021.106743
  12. Wiley Interdiscip Rev RNA. 2022 Jan 30. e1714
    Deep structural insights into RNA-binding disordered protein regions.
    András Zeke, Éva Schád, Tamás Horváth, Rawan Abukhairan, Beáta Szabó, Agnes Tantos.
      Recent efforts to identify RNA binding proteins in various organisms and cellular contexts have yielded a large collection of proteins that are capable of RNA binding in the absence of conventional RNA recognition domains. Many of the recently identified RNA interaction motifs fall into intrinsically disordered protein regions (IDRs). While the recognition mode and specificity of globular RNA binding elements have been thoroughly investigated and described, much less is known about the way IDRs can recognize their RNA partners. Our aim was to summarize the current state of structural knowledge on the RNA binding modes of disordered protein regions and to propose a classification system based on their sequential and structural properties. Through a detailed structural analysis of the complexes that contain disordered protein regions binding to RNA, we found two major binding modes that represent different recognition strategies and, most likely, functions. We compared these examples with DNA binding disordered proteins and found key differences stemming from the nucleic acids as well as similar binding strategies, implying a broader substrate acceptance by these proteins. Due to the very limited number of known structures, we integrated molecular dynamics simulations in our study, whose results support the proposed structural preferences of specific RNA-binding IDRs. To broaden the scope of our review, we included a brief analysis of RNA-binding small molecules and compared their structural characteristics and RNA recognition strategies to the RNA-binding IDRs. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > Small Molecule-RNA Interactions.
    Keywords:  IDP-RNA complex; RNA recognition; RNA structure; intrinsically disordered protein; protein-RNA binding
    DOI:  https://doi.org/10.1002/wrna.1714
  13. Biomol NMR Assign. 2022 Feb 02.
    Backbone NMR resonance assignment of the intrinsically disordered UBact protein from Nitrospira nitrosa.
    Steven M Bonn, David Fushman.
      Ubiquitin signaling in eukaryotes is responsible for a variety of cellular outcomes, most notably proteasomal degradation. A recent bioinformatic study has revealed the existence of a new proteasomal operon in certain gram-negative bacteria phyla. This operon contains genes similar to those included in the prokaryotic ubiquitin-like protein (Pup) proteasomal operon, but do not themselves contain Pup. Instead, they encode for a protein termed UBact with 30% sequence similarity to Pup. Here, we report the near-complete NMR assignment of the backbone and partial assignment of the side chain chemical shifts of the UBact protein from Nitrospira nitrosa. The 1H-15N HSQC spectrum shows a narrow spread of proton NMR signals, characteristic of an intrinsically disordered protein. This chemical shift assignment will facilitate further NMR studies to explore the role of UBact in this new putative proteasomal operon.
    Keywords:  Intrinsically disordered protein; Nitrospira nitrosa; Proteasome; UBact
    DOI:  https://doi.org/10.1007/s12104-022-10070-x
  14. Biomol NMR Assign. 2022 Jan 30.
    Solution NMR backbone assignments of disordered Olduvai protein domain CON1 employing Hα-detected experiments.
    Natasia Paukovich, Morkos A Henen, Alya Hussain, Aaron Issaian, James M Sikela, Kirk C Hansen, Beat Vögeli.
      Olduvai protein domains, encoded by the NBPF gene family, are responsible for the largest increase in copy number of any protein-coding region in the human genome. This has spawned various genetics studies which have linked these domains to human brain development and divergence from our primate ancestors, as well as currently relevant cognitive diseases such as schizophrenia and autism spectrum disorder (ASD). There are six separate Olduvai domains which together form the majority of the various protein products of the NBPF genes. The six domains include three conserved domains (CON1-3), and three human-lineage-specific domains (HLS1-3) which occur in triplet. Here, we present the solution nuclear magnetic resonance backbone assignments for the CON1 domain, which has been linked to the severity of ASD. The data confirm that CON1 is an intrinsically disordered protein (IDP). Additionally, we use innovative Hα-detected experiments which allow us to not only assign the Hα atoms and N atoms of proline residues, but also to assign residues where HN-experiments suffered from peak overlap or broadening.
    Keywords:  Autism; Backbone chemical shift assignment; DUF1220; IDP; Olduvai domain
    DOI:  https://doi.org/10.1007/s12104-022-10068-5
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