Structural basis of the proinflammatory signaling complex mediated by TSLP

  • Nat Struct Mol Biol. 2014 Apr;21(4):375-82. doi: 10.1038/nsmb.2794.
Kenneth Verstraete  1 ,  Loes van Schie  1 ,  Laurens Vyncke  2 ,  Yehudi Bloch  1 ,  Jan Tavernier  2 ,  Ewald Pauwels  3 ,  Frank Peelman  2 ,  Savvas N Savvides  1
Affiliations
  • 1. Unit for Structural Biology, Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry & Microbiology, Ghent University, Ghent, Belgium.
  • 2. Department of Medical Protein Research, Vlaams Interuniversitair Instituut voor Biotechnologie and Ghent University, Ghent, Belgium.
  • 3. Center for Molecular Modeling, Ghent University, Ghent, Belgium.
PMID: 24632570 DOI: 10.1038/nsmb.2794
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.