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

被引：11

作者：

Chen, Wen-Ting ^{[1
,2
]}

Huang, Wen-Yang ^{[1
,2
]}

Chen, Ting ^{[1
,2
]}

Salawu, Emmanuel Oluwatobi ^{[1
,2
,3
]}

Wang, Dongli ^{[4
]}

Lee, Yi-Zong ^{[1
,2
]}

Chang, Yuan-Yu ^{[1
,2
]}

Yang, Lee-Wei ^{[1
,2
,3
]}

Sue, Shih-Che ^{[1
,2
]}

Wang, Xinquan ^{[4
]}

Yin, Hsien-Sheng ^{[1
,2
]}

机构：

[1] Natl Tsing Hua Univ, Inst Bioinformat & Struct Biol, 101,Sect 2,Kuang Fu Rd, Hsinchu 30013, Taiwan

[2] Natl Tsing Hua Univ, Coll Life Sci, 101,Sect 2,Kuang Fu Rd, Hsinchu 30013, Taiwan

[3] Acad Sinica, Taiwan Int Grad Program, Bioinformat Program, Taipei 115, Taiwan

[4] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

关键词：

CRYSTAL-STRUCTURE; IL-6; PRODUCTION; IL-1-BETA; IDENTIFICATION; INDUCTION; SITE; ACTIVATION; PROTEINS; SEQUENCE; IMMUNITY;

D O I：

10.1038/srep27729

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Receptor-binding and subsequent signal-activation of interleukin-1 beta (IL-1 beta) 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-1 beta signaling in vitro but can antagonize wild-type (WT) IL-1 beta. 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-1 beta. Molecular dynamics simulations of IL-1 beta 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-1 beta/IL-1RI/IL-1RAcP signaling complex. We identify the hot spots in IL-1 beta that are essential to immune responses and elucidate a mechanism by which IL-1 beta activity can be inhibited. These findings should aid in the development of new therapeutics that neutralize IL-1 activity.

引用

页数：11

共 42 条

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