Selective Formation of ErbB-2/ErbB-3 Heterodimers Depends on the ErbB-3 Affinity of Epidermal Growth Factor-like Ligands*
Selective Formation of ErbB-2/ErbB-3 Heterodimers Depends on the ErbB-3 Affinity of Epidermal Growth Factor-like Ligands*
复制标题
ErbB-2/ErbB-3 异二聚体的选择性形成取决于表皮生长因子样配体的 ErbB-3 亲和力*
DOI：
--
复制
发表时间：
2003
影响因子：
4.8
通讯作者：
E. J. V. van Zoelen
中科院分区：
文献类型：
--
作者：
C. Stortelers;S. P. van der Woning;Saskia Jacobs;M. Wingens;E. J. V. van Zoelen
EGF样生长因子通过促进受体介导的同源二聚或通过一种未知的机制与孤儿ErbB-2形成异源二聚体来激活其ErbB受体。为了研究配体在二聚体形成中的选择性，我们应用噬菌体展示方法获得了带有修饰的C-末端残基的配体，这些配体区分ErbB-2和ErbB-3作为二聚伙伴。我们使用表皮生长因子/转化生长因子α嵌合体T1E作为模板分子，因为它与低亲和力的ErbB-3同源二聚体和高亲和力的ErbB-2/ErbB-3异二聚体结合。许多噬菌体变异体与ErbB-3同源二聚体的结合亲和力增强，表明C末端残基参与了与ErbB-3的相互作用。这些变异体也是ErbB-2/ErbB-3杂二聚体的有效配体，尽管对此类杂二聚体的选择是否定的。相反，阳性选择与ErbB-2/ErbB-3异二聚体结合而阴性选择结合ErbB-3同源二聚体的噬菌体变异体可被认为是“第二好的”ErbB-3结合体，需要ErbB-2异二聚化才能稳定地形成复合体。我们的发现表明，表皮生长因子样配体通过至少涉及配体的两个线性末端的多结构域相互作用与ErbB-3结合。显然，配基的ErbB-3亲和力决定了它是只能形成ErbB-2/ErbB-3复合体，还是形成ErbB-3同源二聚体。由于没有确定ErbB-2的单独结合结构域，我们的数据支持一个模型，即ErbB通过受体介导的机制而不是通过二价配体发生异二聚化。
EGF-like growth factors activate their ErbB receptors by promoting receptor-mediated homodimerization or, alternatively, by the formation of heterodimers with the orphan ErbB-2 through an as yet unknown mechanism. To investigate the selectivity in dimer formation by ligands, we have applied the phage display approach to obtain ligands with modified C-terminal residues that discriminate between ErbB-2 and ErbB-3 as dimerization partners. We used the epidermal growth factor/transforming growth factor α chimera T1E as the template molecule because it binds to ErbB-3 homodimers with low affinity and to ErbB-2/ErbB-3 heterodimers with high affinity. Many phage variants were selected with enhanced binding affinity for ErbB-3 homodimers, indicating that C-terminal residues contribute to the interaction with ErbB-3. These variants were also potent ligands for ErbB-2/ErbB-3 heterodimers despite negative selection for such heterodimers. In contrast, phage variants positively selected for binding to ErbB-2/ErbB-3 heterodimers but negatively selected for binding to ErbB-3 homodimers can be considered as “second best” ErbB-3 binders, which require ErbB-2 heterodimerization for stable complex formation. Our findings imply that epidermal growth factor-like ligands bind ErbB-3 through a multi-domain interaction involving at least both linear endings of the ligand. Apparently the ErbB-3 affinity of a ligand determines whether it can form only ErbB-2/ErbB-3 complexes or also ErbB-3 homodimers. Because no separate binding domain for ErbB-2 could be identified, our data support a model in which ErbB heterodimerization occurs through a receptor-mediated mechanism and not through bivalent ligands.
DOI：
10.1073/pnas.91.17.8132
发表时间：
1994-08-16
影响因子：
11.1
作者：
GUY, PM;PLATKO, JV;CARRAWAY, KL
通讯作者：
CARRAWAY, KL
直接鉴定紧邻结合的表皮生长因子的氨基末端的表皮生长因子受体的残基。
DOI：
10.1073/pnas.89.16.7801
发表时间：
1992
影响因子：
11.1
作者：
Woltjer,RL;Lukas,TJ;Staros,JV
通讯作者：
Staros,JV