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 -