Orchestration of signaling by structural disorder in class 1 cytokine receptors
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Orchestration of signaling by structural disorder in class 1 cytokine receptors. / Seiffert, Pernille; Bugge, Katrine; Nygaard, Mads; Haxholm, Gitte W.; Martinsen, Jacob H.; Pedersen, Martin N.; Arleth, Lise; Boomsma, Wouter; Kragelund, Birthe B.
In: Cell Communication and Signaling, Vol. 18, No. 1, 132, 24.08.2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Orchestration of signaling by structural disorder in class 1 cytokine receptors
AU - Seiffert, Pernille
AU - Bugge, Katrine
AU - Nygaard, Mads
AU - Haxholm, Gitte W.
AU - Martinsen, Jacob H.
AU - Pedersen, Martin N.
AU - Arleth, Lise
AU - Boomsma, Wouter
AU - Kragelund, Birthe B.
PY - 2020/8/24
Y1 - 2020/8/24
N2 - 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.
AB - 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.
KW - IDRs
KW - IDPs
KW - Signaling
KW - NMR
KW - SAXS
KW - SLiM
KW - Disorder
KW - Structural biology
KW - CIDER
KW - IDDomainSpotter
KW - Cytokine receptors
KW - Transmembrane receptors
KW - COLONY-STIMULATING FACTOR
KW - PROLACTIN RECEPTOR
KW - GROWTH-HORMONE
KW - INTRINSIC DISORDER
KW - ERYTHROPOIETIN RECEPTOR
KW - BINDING-PROTEIN
KW - SHORT FORMS
KW - PHOSPHATIDYLINOSITOL 3-KINASE
KW - SEQUENCE DETERMINANTS
KW - INTRACELLULAR DOMAIN
U2 - 10.1186/s12964-020-00626-6
DO - 10.1186/s12964-020-00626-6
M3 - Journal article
C2 - 32831102
VL - 18
JO - Cell Communication and Signaling
JF - Cell Communication and Signaling
SN - 1478-811X
IS - 1
M1 - 132
ER -
ID: 248851868