title: Structural basis of the proinflammatory signaling complex mediated by TSLP.
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.
authors.affiliation: Unit for Structural Biology, Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry & Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Verstraete
authors.affiliation: Unit for Structural Biology, Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry & Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Loes
authors.initials: L
authors.lastname: van Schie
authors.affiliation: Department of Medical Protein Research, Vlaams Interuniversitair Instituut voor Biotechnologie and Ghent University, Ghent, Belgium.
authors.forename: Laurens
authors.initials: L
authors.lastname: Vyncke
authors.affiliation: Unit for Structural Biology, Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry & Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Yehudi
authors.initials: Y
authors.lastname: Bloch
authors.affiliation: Department of Medical Protein Research, Vlaams Interuniversitair Instituut voor Biotechnologie and Ghent University, Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
authors.affiliation: Center for Molecular Modeling, Ghent University, Ghent, Belgium.
authors.forename: Ewald
authors.initials: E
authors.lastname: Pauwels
authors.affiliation: Department of Medical Protein Research, Vlaams Interuniversitair Instituut voor Biotechnologie and Ghent University, Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Peelman
authors.affiliation: Unit for Structural Biology, Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry & Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Savvas N
authors.initials: SN
authors.lastname: Savvides
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018448:Models, Immunological; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D020395:Receptors, Interleukin-7 / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D007376:Interleukin-2; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D000094632:Thymic Stromal Lymphopoietin