二聚体
配体(生物化学)
生物物理学
构象变化
表皮生长因子受体
受体
表皮生长因子
分子内力
蛋白质结构
生物
立体化学
结晶学
化学
生物化学
有机化学
作者
Jessica Dawson,Mitchell B. Berger,Chun Chi Lin,Joseph Schlessinger,Mark A. Lemmon,Kathryn M. Ferguson
标识
DOI:10.1128/mcb.25.17.7734-7742.2005
摘要
Structural studies have shown that ligand-induced epidermal growth factor receptor (EGFR) dimerization involves major domain rearrangements that expose a critical dimerization arm. However, simply exposing this arm is not sufficient for receptor dimerization, suggesting that additional ligand-induced dimer contacts are required. To map these contributions to the dimer interface, we individually mutated each contact suggested by crystallographic studies and analyzed the effects on receptor dimerization, activation, and ligand binding. We find that domain II contributes >90% of the driving energy for dimerization of the extracellular region, with domain IV adding little. Within domain II, the dimerization arm forms much of the dimer interface, as expected. However, a loop from the sixth disulfide-bonded module (immediately C-terminal to the dimerization arm) also makes a critical contribution. Specific ligand-induced conformational changes in domain II are required for this loop to contribute to receptor dimerization, and we identify a set of ligand-induced intramolecular interactions that appear to be important in driving these changes, effectively "buttressing" the dimer interface. Our data also suggest that similar conformational changes may determine the specificity of ErbB receptor homo- versus heterodimerization.
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