A dimerization hierarchy in the transmembrane domains of the HER receptor family
A dimerization hierarchy in the transmembrane domains of the HER receptor family
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DOI：
10.1021/bi061436f
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发表时间：
2007-02-20
期刊：
影响因子：
2.9
通讯作者：
Sturgis, James N.
中科院分区：
文献类型：
--
作者：
Duneau, Jean-Pierre;Vegh, Attila P.;Sturgis, James N.
Bitopic膜蛋白为研究跨膜结构域相互作用提供了机会，而没有多源整合性膜蛋白固有的结构复杂性。迄今为止，仅对同源性关联进行了广泛的数量研究。在这里，我们建议评估杂体关联的热力学，这为研究特异性和选择性开辟了道路。 EGFR受体家族与可能与不同伴侣相互作用的单个跨膜结构域的生物学相关性系统非常有趣。这四个成员，所有酪氨酸激酶受体，都参与了一个可能导致一组同型和异二聚体的相互作用网络，非常适合这样一项研究。此外，这些受体的跨膜结构域先前已经与跨膜结构域中的突变有关导致本构激活的突变与它们的功能有关。我们使用基于荧光的相互作用能的测量结果证明，跨膜结构域相互作用的层次结构从非相互作用对到强二聚化。我们建议基于EGFR二聚体的晶体结构的结构模型，以说明二聚体结构如何偏爱这些相互作用。我们观察到跨膜结构域和整个受体相互作用层次结构之间的相关性开辟了一个新的视角，这表明了跨膜受体域在受体信号传导调制中的作用。
Bitopic membrane proteins offer an opportunity for studying transmembrane domain interactions without the structural complexity inherent to multitopic integral membrane proteins. To date, only homomeric associations have been extensively studied quantitatively. Here we propose to assess the thermodynamics of heteromeric associations, which opens the way to investigating specificity and selectivity. A very interesting system of biological relevance with single transmembrane domains possibly involved in interactions with different partners is the EGFR receptor family. The four members, all tyrosine kinase receptors, are involved in an interaction network that potentially leads to a complete set of homo- and heterodimers, ideally suited to such a study. Furthermore, the transmembrane domains of these receptors have been previously implicated in their function in the past by mutations in the transmembrane domain leading to constitutive activation. We demonstrate, using a fluorescence-based measurement of interaction energies, a hierarchy of transmembrane domain interactions ranging from a noninteractive pair to strong dimerization. We propose a structural model based on the crystal structure of the EGFR dimer, to show how the dimeric structure favors these interactions. The correlation we observe between transmembrane domain and whole receptor interaction hierarchies opens a new perspective, suggesting a role for transmembrane receptor domains in the modulation of receptor signaling.