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Structural basis of the proinflammatory signaling complex mediated by TSLP.

Verstraete K, van Schie L, Vyncke L, Bloch Y, Tavernier J, Pauwels E, Peelman F, Savvides SN
Nat Struct Mol Biol 21 375-82 (2014)
Related entries: 4nn5, 4nn6

Cited: 27 times
EuropePMC logo PMID: 24632570

Abstract

Thymic stromal lymphopoietin (TSLP), a cytokine produced by epithelial cells at barrier surfaces, is pivotal for the development of widespread chronic inflammatory disorders such as asthma and atopic dermatitis. The structure of the mouse TSLP-mediated signaling complex reveals how TSLP establishes extensive interfaces with its cognate receptor (TSLPR) and the shared interleukin 7 receptor α-chain (IL-7Rα) to evoke membrane-proximal receptor-receptor contacts poised for intracellular signaling. Binding of TSLP to TSLPR is a mechanistic prerequisite for recruitment of IL-7Rα to the high-affinity ternary complex, which we propose is coupled to a structural switch in TSLP at the crossroads of the cytokine-receptor interfaces. Functional interrogation of TSLP-receptor interfaces points to putative interaction hotspots that could be exploited for antagonist design. Finally, we derive the structural rationale for the functional duality of IL-7Rα and establish a consensus for the geometry of ternary complexes mediated by interleukin 2 (IL-2)-family cytokines.

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  2. Humanized mouse models for immuno-oncology research. Chuprin J, Buettner H, Seedhom MO, Greiner DL, Keck JG, Ishikawa F, Shultz LD, Brehm MA. Nat Rev Clin Oncol 20 192-206 (2023)
  3. The βc receptor family - Structural insights and their functional implications. Broughton SE, Nero TL, Dhagat U, Kan WL, Hercus TR, Tvorogov D, Lopez AF, Parker MW. Cytokine 74 247-258 (2015)
  4. Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures. Felix J, Savvides SN. Nat Rev Immunol 17 112-129 (2017)
  5. The Role of Airway Epithelial Cell Alarmins in Asthma. Whetstone CE, Ranjbar M, Omer H, Cusack RP, Gauvreau GM. Cells 11 1105 (2022)
  6. Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer. Marković I, Savvides SN. Front Immunol 11 1557 (2020)
  7. Mechanisms of pre-B-cell receptor checkpoint control and its oncogenic subversion in acute lymphoblastic leukemia. Buchner M, Swaminathan S, Chen Z, Müschen M. Immunol Rev 263 192-209 (2015)
  8. Interleukin-7 Receptor Alpha in Innate Lymphoid Cells: More Than a Marker. Sheikh A, Abraham N. Front Immunol 10 2897 (2019)
  9. Alarmin Cytokines as Central Regulators of Cutaneous Immunity. Hasegawa T, Oka T, Demehri S. Front Immunol 13 876515 (2022)
  10. Structural Perspectives on Extracellular Recognition and Conformational Changes of Several Type-I Transmembrane Receptors. Chataigner LMP, Leloup N, Janssen BJC. Front Mol Biosci 7 129 (2020)

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