Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms.
Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms.
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DOI：
10.1021/acs.biochem.8b00006
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发表时间：
2018-03-06
期刊：
影响因子：
2.9
通讯作者：
Enns CA
中科院分区：
文献类型：
--
作者：
Kleven MD;Jue S;Enns CA
遗传性血色素沉着症 (HH) 是一种以铁调素表达不足导致的慢性铁超负荷为特征的疾病，是最常见的遗传性疾病之一。 HH 的一种形式（III 型）是由转铁蛋白受体 2 (TfR2) 突变引起的。 TfR2 被认为是能够调节铁调素表达的信号系统的一部分。然而，TfR2 在该系统中的作用的分子细节仍不清楚。当 Tf 的铁饱和度较高时，预计 TfR2 会结合铁载体转铁蛋白 (Tf)。为了更好地了解这些 TfR-Tf 相互作用的性质，进行了全长受体的结合研究。与之前对受体截短形式的研究一致，holo-Tf 与同系物 TfR1 的结合明显强于 TfR2。然而，Tf-TfR2 的结合常数仍然远高于生理学 Holo-Tf 水平，与假设模型不一致，表明其他因素介导了相互作用。一种可能的因子 Apo-Tf 在血清 pH 值下仅与 TfR2 结合较弱，因此无法与 Holo-Tf 有效竞争。 Tf 与含有 TfR1 螺旋结构域的 TfR2 嵌合体的结合表明，螺旋结构域的差异导致了 Tf 结合速率的差异，并且非保守的受体间相互作用对于复合物的稳定是必要的。一个可能的稳定位点（顶端臂连接处）的保守残基对于 TfR1-Tf 结合并不重要，但对于 TfR2-Tf 相互作用至关重要。我们的结果突出了 Tf 与两个 TfR 相互作用的差异。
Hereditary hemochromatosis (HH), a disease marked by chronic iron overload from insufficient expression of the hormone hepcidin, is one of the most common genetic diseases. One form of HH (Type III) results from mutations in the transferrin receptor-2 (TfR2). TfR2 is postulated to be a part of signaling system that is capable of modulating hepcidin expression. The molecular details of TfR2’s role in this system remain unclear, however. TfR2 is predicted to bind the iron carrier transferrin (Tf) when the iron-saturation of Tf is high. To better understand the nature of these TfR-Tf interactions, a binding study with the full-length receptors was conducted. In agreement with previous studies with truncated forms of the receptors, holo-Tf binds to the homolog, TfR1, significantly stronger than TfR2. However, the binding constant for Tf-TfR2 is still far above that of physiological holo-Tf levels, inconsistent with the hypothetical model and suggests that other factors mediate the interaction. One possible factor, Apo-Tf, only weakly binds TfR2 at serum pH, thus will not be able to effectively compete with holo-Tf. Tf-binding to a TfR2 chimera containing the TfR1-helical domain indicates that the differences in the helical domain account for differences in on-rate of Tf, and non-conserved inter-receptor interactions are necessary for the stabilization of the complex. Conserved residues at one possible site of stabilization, the apical arm junction, are not important for TfR1-Tf binding, but are critical for the TfR2-Tf interaction. Our results highlight the differences in Tf interactions with the two TfRs.
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