Homodimerization restores biological activity to an inactive erythropoietin mutant

被引:29
作者
Qiu, HW [1 ]
Belanger, A [1 ]
Yoon, HWP [1 ]
Bunn, HF [1 ]
机构
[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Hematol, Boston, MA 02115 USA
关键词
D O I
10.1074/jbc.273.18.11173
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Erythropoietin (Epo) is believed to transduce a signal by bringing two Epo receptors into close proximity, enabling cross-phosphorylation. We compared monomeric Epos with homodimers in which two Epo monomers are linked by polyglycine. Monomeric Epo mutant R103A is unable to support Epo-dependent cell growth or trigger Janus kinase 2 and STATE activation, even at concentrations greater than 7,000 times that sufficient for wildtype Epo activity. In contrast, R103A homodimer induces proliferation and transduces signal at concentrations similar to that of wild-type Epo monomer and homodimer. These experiments show that two discrete domains on Epo are required for receptor binding and activation. Our results also suggest that the EpoR can be dimerized by different forms and sizes of molecules, as long as two recognition moths are provided in the same molecule. Design of other dimeric molecules may enhance our understanding of cytokine specificity and signal transduction.
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收藏
页码:11173 / 11176
页数:4
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