Orchestration of signaling by structural disorder in class 1 cytokine receptors
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(2020) 18:132
RESEARCH
Open Access
Orchestration of signaling by structural disorder in class 1 cytokine receptors Pernille Seiffert1,2†, Katrine Bugge1,2†, Mads Nygaard1,2, Gitte W. Haxholm1,2, Jacob H. Martinsen1,2, Martin N. Pedersen3, Lise Arleth3, Wouter Boomsma4 and Birthe B. Kragelund1,2*
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. Keywords: IDRs, IDPs, Signaling, NMR, SAXS, SLiM, Disorder, Structural biology, CIDER, IDDomainSpotter, Cytokine receptors, Transmembrane receptors
Background The sequencing of the human genome and key observations from earlier research [1, 2], spurred the recognition of proteins and protein regions functioning without having three-dimensional folds. These intrinsically * Correspondence: [email protected] † Pernille Seiffert and Katrine Bugge contributed equally to this work. 1 REPIN, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark 2 Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark Full list of author information is available at the end of the article
disordered proteins (IDPs) and regions (IDRs, collectively here referred to as IDPs), constitute around 30– 40% of the human proteome [3] and perform key cellular and highly regulated processes such as transcription, translation and signaling [4–7]. IDPs show distinct sequence characteristics with higher frequencies of Pro, Glu, Ser, Gln, Lys, Ala, and Gly, a
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