A dual role for the N-terminal domain of the IL-3 receptor in cell signalling

被引：33

作者：

Broughton, Sophie E. ^{[1
]}

Hercus, Timothy R. ^{[2
,3
]}

Nero, Tracy L. ^{[1
]}

Kan, Winnie L. ^{[2
,3
]}

Barry, Emma F. ^{[2
,3
]}

Dottore, Mara ^{[2
,3
]}

Shing, Karen S. Cheung Tung ^{[1
,4
]}

Morton, Craig J. ^{[1
]}

Dhagat, Urmi ^{[1
]}

Hardy, Matthew P. ^{[5
]}

Wilson, Nicholas J. ^{[5
]}

Downton, Matthew T. ^{[6
]}

Schieber, Christine ^{[6
]}

Hughes, Timothy P. ^{[7
,8
]}

Lopez, Angel F. ^{[2
,3
]}

Parker, Michael W. ^{[1
,4
]}

机构：

[1] St Vincents Inst Med Res, Australian Canc Res Fdn, Rat Drug Discovery Ctr, Fitzroy, Vic 3065, Australia

[2] SA Pathol, Ctr Canc Biol, Adelaide, SA 5000, Australia

[3] Univ South Australia, Adelaide, SA 5000, Australia

[4] Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Dept Biochem & Mol Biol, Parkville, Vic 3010, Australia

[5] CSL Ltd, Parkville, Vic 3010, Australia

[6] IBM Res Australia, Level 5,204 Lygon St, Carlton, Vic 3053, Australia

[7] South Australian Hlth & Med Res Inst, Adelaide, SA 5000, Australia

[8] Univ Adelaide, Adelaide, SA 5000, Australia

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国医学研究理事会;

关键词：

ACUTE MYELOID-LEUKEMIA; COLONY-STIMULATING FACTOR; HIGH-AFFINITY BINDING; COMMON BETA-CHAIN; ACUTE MYELOGENOUS LEUKEMIA; HUMAN INTERLEUKIN-3; STEM-CELLS; GM-CSF; MOLECULAR-DYNAMICS; ALPHA-CHAIN;

D O I：

10.1038/s41467-017-02633-7

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：

The interleukin-3 (IL-3) receptor is a cell-surface heterodimer that links the haemopoietic, vascular and immune systems and is overexpressed in acute and chronic myeloid leukaemia progenitor cells. It belongs to the type I cytokine receptor family in which the alpha-subunits consist of two fibronectin III-like domains that bind cytokine, and a third, evolutionarily unrelated and topologically conserved, N-terminal domain (NTD) with unknown function. Here we show by crystallography that, while the NTD of IL3R alpha is highly mobile in the presence of IL-3, it becomes surprisingly rigid in the presence of IL-3 K116W. Mutagenesis, biochemical and functional studies show that the NTD of IL3R alpha regulates IL-3 binding and signalling and reveal an unexpected role in preventing spontaneous receptor dimerisation. Our work identifies a dual role for the NTD in this cytokine receptor family, protecting against inappropriate signalling and dynamically regulating cytokine receptor binding and function.

引用

页数：15

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