Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation

Ferrao, Ryan; Wallweber, Heidi J.A.; Lupardus, P.J.

doi:10.7554/elife.38089

Cited by 52 publications

(53 citation statements)

References 57 publications

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“…Interestingly, in the solved structure of the FERM-SH2 domain of TYK2 complexed with IFNAR1 (Fig S1B), this segment does not directly contact the receptor [23, 24]. This segment is likely exposed at the surface of the F3 lobe of the FERM and contains a disordered loop (β3-β4 loop), unusually long among the JAK proteins (Fig 1C), which may provide critical contact points for cognate receptors [25].…”

Section: Resultsmentioning

confidence: 99%

Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage

Rotival

Patin

et al. 2019

Preprint

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23 TYK2 belongs to the JAK protein tyrosine kinase family and mediates signaling of numerous 24 antiviral and immunoregulatory cytokines (type I and type III IFNs, IL-10, IL-12, IL-22, IL-25 23) in immune and non-immune cells. After many years of genetic association studies, TYK2 26 is recognized as a susceptibility gene for some inflammatory and autoimmune diseases (AID).27 Seven TYK2 variants have been associated with AIDs in Europeans, and establishing their 28 causality remains challenging. Previous work showed that a protective variant (P1104A) is 29 hypomorphic and also a risk allele for mycobacterial infection. Here, we have studied two 30 AID-associated common TYK2 variants: rs12720270 located in intron 7 and rs2304256, a 31 non-synonymous variant in exon 8 that causes a valine to phenylalanine substitution (c.1084 32 G > T, Val362Phe). We found that this amino acid substitution does not alter TYK2 33 expression, catalytic activity or ability to relay signaling in EBV-B cell lines or in 34 reconstituted TYK2-null cells. Based on in silico predictions that these variants may impact 35 splicing of exon 8, we: i) analyzed TYK2 transcripts in genotyped EBV-B cells and in 36 CRISPR/Cas9-edited cells, ii) measured splicing using minigene assays, and iii) performed 37 eQTL (expression quantitative trait locus) analysis of TYK2 transcripts in primary monocytes 38 and whole blood cells. Our results reveal that the two variants promote the inclusion of exon 39 8, which, we demonstrate, is essential for TYK2 binding to cognate receptors. In addition and 40 in line with GTEx (Genetic Tissue Expression) data, our eQTL results show that rs2304256 41 mildly enhances TYK2 expression in whole blood. In all, these findings suggest that these 42 TYK2 variants are not neutral but instead have a potential impact in AID. 3 43 Introduction 44 Early genetic association studies have assigned to the TYK2 locus an impact on susceptibility 45 to systemic lupus erythematosus (SLE) and other autoimmune diseases (AID). The 46 identification has been replicated in a number of recent analyses, and TYK2 is now recognized 47 as a susceptibility gene in a variety of inflammatory and autoimmune diseases, including type 48 I diabetes (T1D), psoriasis and multiple sclerosis (Table 1). These chronic disorders have a 49 complex etiology where combinations of genetic and environmental factors eventually lead to 50 loss of immunological tolerance, chronic immune activation, and damage to one organ or 51 several tissues [1]. 52How TYK2 variants impact disease onset or progression remains an open question. In 53 human populations, the TYK2 locus presents with thousands of single nucleotide 54 polymorphisms (SNP), of which more than 500 cause non-synonymous (amino acid-altering) 55 changes. Seven TYK2 variants have been associated with AIDs in European cohorts and for 56 most the minor allele is protective (Table 1). Notably, rs12720356 (I684S) is protective for 57 some AID but risky for others, which suggests different underlying pathogenic mechanis...

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Section: Resultsmentioning

confidence: 99%

Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage

Rotival

Patin

et al. 2019

Preprint

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“…Interestingly, in the solved structure of the FERM-SH2 domain of TYK2 complexed with IFNAR1 (S1B Fig), this segment does not directly contact the receptor [23,24]. This segment is likely exposed at the surface of the F3 lobe of the FERM and contains a disordered loop (β3-β4 loop), unusually long among the JAK proteins ( Fig 1C), which may provide critical contact points for cognate receptors [25]. Phosphorylated TYK2 in the reaction was revealed by immunoblotting with anti-phospho-TYK2.…”

Section: Tyk2-δe8 Is Catalytically Competent But Unable To Mediate Cymentioning

confidence: 99%

Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage

Rotival

Patin

et al. 2020

PLoS ONE

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TYK2 belongs to the JAK protein tyrosine kinase family and mediates signaling of numerous antiviral and immunoregulatory cytokines (type I and type III IFNs, IL-10, IL-12, IL-22, IL-23) in immune and non-immune cells. After many years of genetic association studies, TYK2 is recognized as a susceptibility gene for some inflammatory and autoimmune diseases (AID). Seven TYK2 variants have been associated with AIDs in Europeans, and establishing their causality remains challenging. Previous work showed that a protective variant (P1104A) is hypomorphic and also a risk allele for mycobacterial infection. Here, we have studied two AID-associated common TYK2 variants: rs12720270 located in intron 7 and rs2304256, a non-synonymous variant in exon 8 that causes a valine to phenylalanine substitution (c.1084 G > T, Val362Phe). We found that this amino acid substitution does not alter TYK2 expression, catalytic activity or ability to relay signaling in EBV-B cell lines or in reconstituted TYK2-null cells. Based on in silico predictions that these variants may impact splicing of exon 8, we: i) analyzed TYK2 transcripts in genotyped EBV-B cells and in CRISPR/Cas9edited cells, ii) measured splicing using minigene assays, and iii) performed eQTL (expression quantitative trait locus) analysis of TYK2 transcripts in primary monocytes and whole blood cells. Our results reveal that the two variants promote the inclusion of exon 8, which, we demonstrate, is essential for TYK2 binding to cognate receptors. In addition and in line with GTEx (Genetic Tissue Expression) data, our eQTL results show that rs2304256 mildly enhances TYK2 expression in whole blood. In all, these findings suggest that these TYK2 variants are not neutral but instead have a potential impact in AID.

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“…Still, no structural information is at all available for almost one fourth of the receptors, including the TPOR, interleukin (IL)-31Rb, IL-31Ra, IL-12Rb1, IL-12Rb2, IL-27R, IL-9Ra, IL-11Ra, and the oncostatin-M-speci c receptor (OSMR). Furthermore, only six structures are available of shorter fragments of ICDs in complex with signaling molecules, as exempli ed by the juxtamembrane domain of the EPOR in complex with the FERM-SH2 domains of JAK2 [44], a 12-residue phospho-peptide from GHR-ICD in complex with SOCS2 [79], an 11-residue phospho-peptide of IL-4R-ICD with the phospho-tyrosine binding domain of the insulin receptor substrate (IRS)-1 [80], and an 8-residue peptide from IL-5Ra-ICD with the PDZ domain of syntenin [81], Fig. 1b.…”

Section: Structural Biology Of C1crsmentioning

confidence: 99%

“…Except for group 5, which lacks canonical Box1 and Box2 motifs, all receptors harbor the conserved PXP motif in Box1 (SI Fig. S4), known to interact with the JAK-FERM domain [44,123]. However, in most receptors, Box1 is further extended to PXXPXP (consensus for group 1: jjPXjPXP, where j is any hydrophobic residue), which thereby accommodates both the minimal SH3 binding motif (PXXP) [124] and the FERM binding motif (PXP) in one combined SLiM (Table 2).…”

Section: Short Linear Motifs Allow Expansion Of the Interactomementioning

confidence: 99%

“…Interactions by IDPs are often mediated by short linear motifs (SLiMs), which are 2-12 residue sequence stretches that are typically recognized by patterns of conserved residues within an otherwise sparsely conserved sequence stretch [12]. SLiMs may overlap, and due to the structural plasticity of disordered regions, transiently exposed motifs and binding interfaces thus provide a trait of JAK1/2 and TYK2 and a fragment of a cytokine receptor ICD were solved, namely of the erythropoietin receptor (EPOR) [44] ( Fig. 1b), and of two class II cytokine receptors ICDs from the interferon-l receptor 1 ( IFNLR1) [45] and interferon-a receptor chain 1 (IFNAR-1) [46], respectively (positions and structures shown together on an prototypical receptor in Fig.…”

Section: Introductionmentioning

confidence: 99%

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Orchestration of signaling by structural disorder in class 1 cytokine receptors

Seiffert

Bugge

Nygaard

et al. 2020

Preprint

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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 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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Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation

Cited by 52 publications

References 57 publications

Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage

Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage

Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage

Orchestration of signaling by structural disorder in class 1 cytokine receptors

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