a cytokine–cytokine interaction in the assembly of higher-order structure and activation of the interleukine-3receptor complexcytokine-cytokine交互的高阶结构的组装和激活interleukine-3receptor复杂.pdfVIP

A Cytokine–Cytokine Interaction in the Assembly of Higher-Order Structure and Activation of the Interleukine-3:Receptor Complex 1 2 2 1 Raja Dey , Kunmei Ji , Zhigang Liu , Lin Chen * 1 Department of Biological Sciences, Molecular and Computational Biology, University of Southern California, Los Angeles, California, United States of America, 2 Institute of Allergy and Immunology, School of Medicine, Shenzhen University, Shenzhen, Guangdong, China Abstract Interleukine-3 (IL-3) binds its receptor and initiates a cascade of signaling processes that regulate the proliferation and differentiation of hematopoietic cells. To understand the detailed mechanisms of IL-3 induced receptor activation, we generated a homology model of the IL-3:receptor complex based on the closely related crystal structure of the GM- CSF:receptor complex. Model-predicted interactions between IL-3 and its receptor are in excellent agreement with mutagenesis data, which validate the model and establish a detailed view of IL-3:receptor interaction. The homology structure reveals an IL-3:IL-3 interaction interface in a higher-order complex modeled after the dodecamer of the GM- CSF:receptor complex wherein an analogous GM-CSF:GM-CSF interface is also identified. This interface is mediated by a proline-rich hydrophobic motif (PPLPLL) of the AA9 loop that is highly exposed in the structure of isolated IL-3. Various experimental data suggest that this motif is required for IL-3 function through receptor-binding independent mechanisms. These observations are consistent with structure-function studies of the GM-CSF:receptor complex showing that formation of the higher-order cytokine:receptor complex is requi