Structure and function of chicken interleukin-1 beta mutants: uncoupling of receptor binding and in vivo biological activity

Receptor-binding and subsequent signal-activation of interleukin-1 beta (IL-1β) are essential to immune and proinflammatory responses. We mutated 12 residues to identify sites important for biological activity and/or receptor binding. Four of these mutants with mutations in loop 9 (T117A, E118K, E11...

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Published in:Scientific reports 2016-06, Vol.6 (1), p.27729-27729, Article 27729
Main Authors: Chen, Wen-Ting, Huang, Wen-Yang, Chen, Ting, Salawu, Emmanuel Oluwatobi, Wang, Dongli, Lee, Yi-Zong, Chang, Yuan-Yu, Yang, Lee-Wei, Sue, Shih-Che, Wang, Xinquan, Yin, Hsien-Sheng
Format: Article
Language:English
Subjects:
13/21
631/250/127/1213
631/535/1266
82/103
82/80
82/83
Biological activity
Cytokines
Hormones
Humanities and Social Sciences
Hydrogen bonds
multidisciplinary
Mutagenesis
Plasma
Poultry
Proteins
Science
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Summary:Receptor-binding and subsequent signal-activation of interleukin-1 beta (IL-1β) are essential to immune and proinflammatory responses. We mutated 12 residues to identify sites important for biological activity and/or receptor binding. Four of these mutants with mutations in loop 9 (T117A, E118K, E118A, E118R) displayed significantly reduced biological activity. Neither T117A nor E118K mutants substantially affected receptor binding, whereas both mutants lack the IL-1β signaling in vitro but can antagonize wild-type (WT) IL-1β. Crystal structures of T117A, E118A and E118K revealed that the secondary structure or surface charge of loop 9 is dramatically altered compared with that of wild-type chicken IL-1β. Molecular dynamics simulations of IL-1β bound to its receptor (IL-1RI) and receptor accessory protein (IL-1RAcP) revealed that loop 9 lies in a pocket that is formed at the IL-1RI/IL-1RAcP interface. This pocket is also observed in the human ternary structure. The conformations of above mutants in loop 9 may disrupt structural packing and therefore the stability in a chicken IL-1β/IL-1RI/IL-1RAcP signaling complex. We identify the hot spots in IL-1β that are essential to immune responses and elucidate a mechanism by which IL-1β activity can be inhibited. These findings should aid in the development of new therapeutics that neutralize IL-1 activity.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep27729