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      Orchestration of signaling by structural disorder in class 1 cytokine receptors

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          Abstract

          Background

          Class 1 cytokine receptors (C1CRs) are single-pass transmembrane proteins responsible for transmitting signals between the outside and the inside of cells. Remarkably, they orchestrate key biological processes such as proliferation, differentiation, immunity and growth through long disordered intracellular domains (ICDs), but without having intrinsic kinase activity. Despite these key roles, their characteristics remain rudimentarily understood.

          Methods

          The current paper asks the question of why disorder has evolved to govern signaling of C1CRs by reviewing the literature in combination with new sequence and biophysical analyses of chain properties across the family.

          Results

          We uncover that the C1CR-ICDs are fully disordered and brimming with SLiMs. Many of these short linear motifs (SLiMs) are overlapping, jointly signifying a complex regulation of interactions, including network rewiring by isoforms. The C1CR-ICDs have unique properties that distinguish them from most IDPs and we forward the perception that the C1CR-ICDs are far from simple strings with constitutively bound kinases. Rather, they carry both organizational and operational features left uncovered within their disorder, including mechanisms and complexities of regulatory functions.

          Conclusions

          Critically, the understanding of the fascinating ability of these long, completely disordered chains to orchestrate complex cellular signaling pathways is still in its infancy, and we urge a perceptional shift away from the current simplistic view towards uncovering their full functionalities and potential.

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          Most cited references117

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          Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm.

          A major challenge in the post-genome era will be determination of the functions of the encoded protein sequences. Since it is generally assumed that the function of a protein is closely linked to its three-dimensional structure, prediction or experimental determination of the library of protein structures is a matter of high priority. However, a large proportion of gene sequences appear to code not for folded, globular proteins, but for long stretches of amino acids that are likely to be either unfolded in solution or adopt non-globular structures of unknown conformation. Characterization of the conformational propensities and function of the non-globular protein sequences represents a major challenge. The high proportion of these sequences in the genomes of all organisms studied to date argues for important, as yet unknown functions, since there could be no other reason for their persistence throughout evolution. Clearly the assumption that a folded three-dimensional structure is necessary for function needs to be re-examined. Although the functions of many proteins are directly related to their three-dimensional structures, numerous proteins that lack intrinsic globular structure under physiological conditions have now been recognized. Such proteins are frequently involved in some of the most important regulatory functions in the cell, and the lack of intrinsic structure in many cases is relieved when the protein binds to its target molecule. The intrinsic lack of structure can confer functional advantages on a protein, including the ability to bind to several different targets. It also allows precise control over the thermodynamics of the binding process and provides a simple mechanism for inducibility by phosphorylation or through interaction with other components of the cellular machinery. Numerous examples of domains that are unstructured in solution but which become structured upon binding to the target have been noted in the areas of cell cycle control and both transcriptional and translational regulation, and unstructured domains are present in proteins that are targeted for rapid destruction. Since such proteins participate in critical cellular control mechanisms, it appears likely that their rapid turnover, aided by their unstructured nature in the unbound state, provides a level of control that allows rapid and accurate responses of the cell to changing environmental conditions. Copyright 1999 Academic Press.
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            Comparative genomics of the eukaryotes.

            A comparative analysis of the genomes of Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae-and the proteins they are predicted to encode-was undertaken in the context of cellular, developmental, and evolutionary processes. The nonredundant protein sets of flies and worms are similar in size and are only twice that of yeast, but different gene families are expanded in each genome, and the multidomain proteins and signaling pathways of the fly and worm are far more complex than those of yeast. The fly has orthologs to 177 of the 289 human disease genes examined and provides the foundation for rapid analysis of some of the basic processes involved in human disease.
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              The molecular details of cytokine signaling via the JAK/STAT pathway

              More than 50 cytokines signal via the JAK/STAT pathway to orchestrate hematopoiesis, induce inflammation and control the immune response. Cytokines are secreted glycoproteins that act as intercellular messengers, inducing proliferation, differentiation, growth, or apoptosis of their target cells. They act by binding to specific receptors on the surface of target cells and switching on a phosphotyrosine‐based intracellular signaling cascade initiated by kinases then propagated and effected by SH2 domain‐containing transcription factors. As cytokine signaling is proliferative and often inflammatory, it is tightly regulated in terms of both amplitude and duration. Here we review molecular details of the cytokine‐induced signaling cascade and describe the architectures of the proteins involved, including the receptors, kinases, and transcription factors that initiate and propagate signaling and the regulatory proteins that control it.
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                Author and article information

                Contributors
                pernille.seiffert@bio.ku.dk
                katrine.bugge@bio.ku.dk
                Nygaard.mads@gmail.com
                gittehaxholm@hotmail.com
                jacob.martinsen@bio.ku.dk
                martinnors@nbi.ku.dk
                arleth@nbi.ku.dk
                wb@di.ku.dk
                bbk@bio.ku.dk
                Journal
                Cell Commun Signal
                Cell Commun. Signal
                Cell Communication and Signaling : CCS
                BioMed Central (London )
                1478-811X
                24 August 2020
                24 August 2020
                2020
                : 18
                : 132
                Affiliations
                [1 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, REPIN, Department of Biology, , University of Copenhagen, ; Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark
                [2 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Structural Biology and NMR Laboratory, Department of Biology, , University of Copenhagen, ; Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark
                [3 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Niels Bohr Institute, University of Copenhagen, ; Blegdamsvej 17, 2100 Copenhagen Ø, Denmark
                [4 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Department of Computer Science, , University of Copenhagen, ; Universitetsparken 1, 2100 Copenhagen Ø, Denmark
                Author information
                http://orcid.org/0000-0002-7454-1761
                Article
                626
                10.1186/s12964-020-00626-6
                7444064
                32831102
                3da80ffa-0cf6-4b2a-b8b3-db83ee55946d
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 29 April 2020
                : 8 July 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100009708, Novo Nordisk Fonden;
                Award ID: #NNF18OC0033926
                Award Recipient :
                Funded by: Novo Nordisk Fonden (DK)
                Award ID: #NNF15OC0016670
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Cell biology
                idrs,idps,signaling,nmr,saxs,slim,disorder,structural biology,cider,iddomainspotter,cytokine receptors,transmembrane receptors

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