The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand
The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand
复制标题
在没有配体的情况下，ErbB4 的细胞外区域采用系留构象
DOI：
10.1073/pnas.0507591102
复制
发表时间：
2005-10-18
影响因子：
11.1
通讯作者：
Leahy, DJ
中科院分区：
文献类型：
--
作者：
Bouyain, S;Longo, PA;Leahy, DJ
人 ErbB 受体酪氨酸激酶家族包括表皮生长因子受体 (EGFR/ErbB1/HER1)、ErbB2 (HER2/Neu)、ErbB3 (HER3) 和 ErbB4 (HER4)。 ErbB 在胚胎和成体组织的细胞生长和分化事件中发挥着重要作用，并且不适当的 ErbB 活性与多种人类癌症有关。我们在这里报告了在没有配体的情况下人 ErbB4 细胞外区域的 2.4 埃晶体结构，并表明它采用类似于 ErbB1 和 ErbB3 的非活性形式的束缚构象。该结构完善了未配体 ErbB 受体的库，并证明所有人类配体结合 ErbB 均采用自抑制构象。我们还表明，神经调节蛋白-1β与ErbB4和ErbB3的结合以及βcellulin与ErbB4和ErbB1的结合在低pH下不会减少，这与表皮生长因子和转化生长因子-α与ErbB1的结合不同。这些结果表明配体在确定 pH 依赖性结合中的重要作用，并且可以解释当相同 ErbB 受体被不同配体刺激时观察到的不同反应。
The human ErbB family of receptor tyrosine kinases comprises the epidermal growth factor receptor (EGFR/ErbB1/HER1), ErbB2 (HER2/Neu), ErbB3 (HER3), and ErbB4 (HER4). ErbBs play fundamental roles in cell growth and differentiation events in embryonic and adult tissues, and inappropriate ErbB activity has been implicated in several human cancers. We report here the 2.4 angstrom crystal structure of the extracellular region of human ErbB4 in the absence of ligand and show that it adopts a tethered conformation similar to inactive forms of ErbB1 and ErbB3. This structure completes the gallery of unliganded ErbB receptors and demonstrates that all human ligand-binding ErbBs adopt the autoinhibited conformation. We also show that the binding of neuregulin-1 beta to ErbB4 and ErbB3 and the binding of betacellulin to both ErbB4 and ErbB1 does not decrease at low pH, unlike the binding of epidermal growth factor and transforming growth factor-alpha to ErbB1. These results indicate an important role for ligand in determining pH-dependent binding and may explain different responses observed when the same ErbB receptor is stimulated by different ligands.