Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands

Moraga, Ignacio; Wernig, Gerlinde; Wilmes, Stephan; Gryshkova, Vitalina; Richter, Christian; Hong, Wan‐Jen; Sinha, Rahul; Guo, Feng; Fabionar, Hyna; Wehrman, Tom S.; Krutzik, Peter O.; Demharter, Samuel; Plo, Isabelle; Weissman, Irving L.; Mináry, Péter; Majeti, Ravindra; Constantinescu, Stefan N.; Piehler, Jacob; García, K. Christopher

doi:10.1016/j.cell.2015.02.011

Cited by 144 publications

(232 citation statements)

References 97 publications

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“…For EPOR the orientation of the transmembrane domains seems to be important for signaling (61,64). Still, using diabodies has shown that these orientation requirements are liberal, absorbing large changes in receptor conformation while maintaining signaling (65).…”

Section: Discussionmentioning

confidence: 99%

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Sharma

Longjam

Schreiber

2016

Journal of Biological Chemistry

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Type I interferons serve as the first line of defense against pathogen invasion. Binding of IFNs to its receptors, IFNAR1 and IFNAR2, is leading to activation of the IFN response. To determine whether structural perturbations observed during binding are propagated to the cytoplasmic domain, multiple mutations were introduced into the transmembrane helix and its surroundings. Insertion of one to five alanine residues near either the N or C terminus of the transmembrane domain (TMD) likely promotes a rotation of 100°and a translation of 1.5 Å per added residue. Surprisingly, the added alanines had little effect on the binding affinity of IFN to the cell surface receptors, STAT phosphorylation, or gene induction. Similarly, substitution of the juxtamembrane residues of the TMD with alanines, or replacement of the TMD of IFNAR1 with that of IFNAR2, did not affect IFN binding or activity. Finally, only the addition of 10 serine residues (but not 2 or 4) between the extracellular domain of IFNAR1 and the TMD had some effect on signaling. Bioinformatic analysis shows a correlation between high sequence conservation of TMDs of cytokine receptors and the ability to transmit structural signals. Sequence conservation near the TMD of IFNAR1 is low, suggesting limited functional importance for this region. Our results suggest that IFN binding to the extracellular domains of IFNAR1 and IFNAR2 promotes proximity between the intracellular domains and that differential signaling is a function of duration of activation and affinity of binding rather than specific conformational changes transmitted from the outside to the inside of the cell.Type I interferons (IFNs) orchestrate the antiviral innate immunity in vertebrates. They consist of 16 members in humans as follows: 12 different IFN␣ subtypes, as well as IFN␤, IFN, IFN⑀, and IFN. They are clustered on the short arm of chromosome 9. All type I interferons elicit their innate and adaptive immune responses after binding to the receptor and forming the IFNAR1-IFN-IFNAR2 ternary complex (1, 2), the formation of which is essential for signaling. Both IFNAR1 and IFNAR2 belong to the class II helical cytokine receptors with four fibronectin type III-like subdomains for IFNAR1 and two subdomains for IFNAR2. The extracellular domains are followed by a single helix of 21 amino acids spanning the membrane, which in turn is connected to mostly natively unstructured intracellular domains and their associated effectors (Fig. 1A) (3). Cells lacking one of the receptors lack normal IFN signaling (4, 5). Structurally different members of type I IFNs bind to the same cell surface receptor but mediate differential responses that result from differences in binding affinities, concentration of IFN, and duration of activation (5-13). Differential signaling is realized through robust (antiviral) versus tunable (antiproliferative and immunomodulatory) gene induction leading to different phenotypic outcomes (14,15). Receptor dimerization drives the activation of cytosolic associated Janus family kina...

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Section: Discussionmentioning

confidence: 99%

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Sharma

Longjam

Schreiber

2016

Journal of Biological Chemistry

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“…Thus, a norrin complex may perhaps even bring the FZD CRD and LRP5/6 β-propeller in contact, while classical Wnts will mediate CRD interactions through the palmitoleoyl modification while binding LRP5/6 through a negatively charged surface relatively distant from the site of CRD contact. The anticipated result would be a tunable and diverse mechanism for the complex activation of the FZD receptor and LRP5/6, which may have significant implications for the design of effective Wnt pathway surrogates and inhibitors (Moraga et al, 2015).The mechanisms of LRP5/6 intracellular activation and interactions with Dishevelled have been excellently described and reviewed elsewhere (Bilic et al, 2007;Bienz, 2014;Feng and Gao, 2015). The role of LRP5/6 clustering to trigger CK1γ phosphorylation and Axin recruitment, the role of Dishevelled stabilization at the LRP/FZD scaffold and the significance of Dishevelled/Axin co-polymerization are not the focus of this review, yet they are all requirements for sequestration of the β-catenin destruction complex and activation of nuclear β-catenin signalling.…”

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confidence: 99%

Assembly and architecture of the Wnt/β‐catenin signalosome at the membrane

DeBruine

Melcher

2017

British J Pharmacology

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Wnt/β-catenin signalling is initiated by a ternary Wnt-Frizzled (FZD)-LDL receptor-related protein (LRP) 5/6 binding event. The resulting conformational changes in the FZD and LRP5/6 receptors promote the assembly of an intracellular signalosome driven by Dishevelled and Axin co-polymerization. Recent evidence suggests that the FZD receptor and LRP5/6 participate in the assembly of this signalosome by forming regulatory scaffolds for stabilizing Dishevelled and Axin adapters. In this review, we focus on the contributions of Wnts and their receptors in the assembly of the signalosome. We present an emerging model, which unifies Wnt receptor oligomerization with intracellular signalosome formation, and then discuss how FZD receptors might be targeted to either disrupt or enhance their capacity as a dynamic sensor of Wnt binding. LINKED ARTICLESThis article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc IntroductionWingless/int1 (Wnt) signal activation is tightly controlled by a dynamic signalosome consisting of Class Frizzled GPCRs (FZDs), LDL receptor-related protein (LRP) 5/6 coreceptors and Dishevelled and Axin adapters (Cong et al., 2004;Kaykas et al., 2004;Bilic et al., 2007;Gammons et al., 2016a). In this review, we discuss emerging evidence for a model of FZD and LRP5/6 co-oligomerization. In this model, oligomerization of the Wnt signalling complex is facilitated by domains with weak homo-oligomerization propensities such as the FZD cysteine-rich domain (CRD), the LRP5/6 β-propeller (βP) domains, and the Dishevelled EGL-10 and pleckstrin (DEP) and Dishevelled and Axin (DIX) domains (Dann et al., 2001;Gammons et al., 2016b). In the absence of Wnt, inactive complexes of FZD, LRP5/6 and DVL pose as static sensors for Wnt binding (Chen et al., 2014) ( Figure 1A). When Wnt binds FZD receptors and LRP5/6, the FZD receptor and LRP5/6 complexes are activated and oligomerize to create an extensive scaffold for Dishevelled stabilization and interaction with LRP5/6 (Bilic et al., 2007) ( Figure 1B). Dishevelled then co-polymerizes with Axin through shared DIX domains to form a trap which sequesters the β-catenin destruction complex (Schwarz-Romond et al., 2007;Fiedler et al., 2011).Consequentially, β-catenin translocates to the nucleus where it works in concert with Wnt transcription factors to turn on Wnt target genes (van de Wetering et al., 1991). Wnt family ligands are FZD-specific, highly conserved and often determine developmental patterning and cell fate (van de Wetering et al., 1997). Many of these physiological consequences are the result of Wnt/β-catenin signalling which involves the assembly of an intracellular Dishevelled/Axin signalosome (Cong et al., 2004; SchwarzRomond et al., 2007). Unlike norrin, an atypical FZD 4 / LRP5 agonist, all 19 human Wnts share a highly conserved two-domain structure which enables it to attach the FZD receptor CRD and bin...

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“…Due to their ability to bind complex epitopes and escape host immune detection, humanized antibody scaffolds were chosen to develop as AcCS. Notably, AcCS are mechanistically and functional distinct from agonistic antibodies, which function as cytokine mimics with similar toxicity issues of normal cytokines (11,12). In contrast, AcCS are designed to increase cytokine activity only when cytokines are bound to their cell surface receptors.…”

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confidence: 99%

Cytokine Activation by Antibody Fragments Targeted to Cytokine-Receptor Signaling Complexes

Kuruganti

Miersch

Deshpande

et al. 2016

Journal of Biological Chemistry

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Background: Cytokines are administered to patients to eliminate viral infections and cancer yet often have side effects. Results: Antibody fragments have been designed that recognize cytokine-receptor complexes and change cytokine biological activity profiles. Conclusion: Designed proteins enhance interferon antiviral activity without inducing antiproliferative signaling pathways. Significance: Antibody fragments targeted to cytokine-receptor complexes provide new tools for manipulating cytokine signaling.

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Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands

Cited by 144 publications

References 97 publications

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Assembly and architecture of the Wnt/β‐catenin signalosome at the membrane

Cytokine Activation by Antibody Fragments Targeted to Cytokine-Receptor Signaling Complexes

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