PMID: 24632570

 

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Title : Structural basis of the proinflammatory signaling complex mediated by TSLP

Abstract :

1. 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
2. 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
3. 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
4. Functional interrogation of TSLP-receptor interfaces points to putative interaction hotspots that could be exploited for antagonist design
5. 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