Molecular architecture of the ErbB2 extracellular domain homodimer.
Molecular architecture of the ErbB2 extracellular domain homodimer.
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DOI：
10.18632/oncotarget.2713
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发表时间：
2015-01-30
期刊：
影响因子：
--
通讯作者：
Guo Y
中科院分区：
文献类型：
--
作者：
Hu S;Sun Y;Meng Y;Wang X;Yang W;Fu W;Guo H;Qian W;Hou S;Li B;Rao Z;Lou Z;Guo Y
人表皮生长因子受体(HERS或ERBbs)在多种细胞过程中发挥重要作用。ERBB2是ErbB家族的关键成员，其过度表达被认为是一种常见的分子异常。在癌症中，这种过度表达与侵袭性疾病和糟糕的患者预后相关。二聚体依赖的磷酸化是ERBBS信号转导的关键事件。然而，ErbB2二聚化的分子机制仍然不清楚。在目前的工作中，我们报道了ErbB2胞外区(ECD)的同源二聚体结构，与其他ERBBS二聚体模型相比是独一无二的。ErbB2ECD同源二聚体的结构代表了一种“背对头”的相互作用，即在一个ErbB2原聚体的结构域II中，一个突出的β-发夹臂插入到由相邻ErbB2原聚体的结构域I-III形成的C形口袋中。突变研究进一步证实了这种二聚化结构及其对ErbB2胞内结构域磷酸化的影响。我们还阐明了两种临床使用的治疗性抗体曲妥珠单抗和pertuzumab对ErbB2二聚化的不同影响。这些信息不仅提供了对ERBBS二聚化的分子机制的了解，而且还在分子水平上阐明了ErbB2的靶向治疗。
Human epidermal growth factor receptors (HERs or ErbBs) play crucial roles in numerous cellular processes. ErbB2 is a key member of ErbB family, and its overexpression is recognized as a frequent molecular abnormality. In cancer, this overexpression correlates with aggressive disease and poor patient outcomes. Dimer-dependent phosphorylation is a key event for the signal transduction of ErbBs. However, the molecular mechanism of the dimerization of ErbB2 remains elusive. In the present work, we report the homodimer architecture of the ErbB2 extracellular domain (ECD) which is unique compared with other dimer-models of ErbBs. The structure of the ErbB2 ECD homodimer represents a “back to head” interaction, in which a protruding β-hairpin arm in domain II of one ErbB2 protomer is inserted into a C-shaped pocket created by domains I–III of the adjacent ErbB2 protomer. This dimerized architecture and its impact on the phosphorylation of ErbB2 intracellular domain were further verified by a mutagenesis study. We also elucidated the different impacts of two clinically administered therapeutic antibodies, trastuzumab and pertuzumab, on ErbB2 dimerization. This information not only provides an understanding of the molecular mechanism of ErbBs dimerization but also elucidates ErbB2-targeted therapy at the molecular level.
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影响因子：
50.3
作者：
Agus, DB;Akita, RW;Sliwkowski, MX
通讯作者：
Sliwkowski, MX
影响因子：
16
作者：
Garrett, TPJ;McKern, NM;Ward, CW
通讯作者：
Ward, CW
DOI：
10.1196/annals.1430.003
发表时间：
2008-01-01
期刊：
FLUORESCENCE METHODS AND APPLICATIONS: SPECTROSCOPY, IMAGING, AND PROBES
影响因子：
--
作者：
Diermeier-Daucher, Simone;Hasmann, Max;Brockhoff, Gero
通讯作者：
Brockhoff, Gero
影响因子：
64.5
作者：
Garrett, TPJ;McKern, NM;Ward, CW
通讯作者：
Ward, CW
影响因子：
3.5
作者：
Alroy, I;Yarden, Y
通讯作者：
Yarden, Y