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.

journal_name

Nat Struct Mol Biol

authors

Verstraete K,van Schie L,Vyncke L,Bloch Y,Tavernier J,Pauwels E,Peelman F,Savvides SN

doi

10.1038/nsmb.2794

subject

Has Abstract

pub_date

2014-04-01 00:00:00

pages

375-82

issue

4

eissn

1545-9993

issn

1545-9985

pii

nsmb.2794

journal_volume

21

pub_type

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