Kawabata Hiroshi, Tong Xiangjun, Kawanami Takafumi, Wano Yuji, Hirose Yuko, Sugai Susumu, Koeffler H Phillip
Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Br J Haematol. 2004 Nov;127(4):464-73. doi: 10.1111/j.1365-2141.2004.05224.x.
Transferrin receptor 2 alpha (TfR2 alpha), the major product of the TfR2 gene, is the second receptor for transferrin (Tf), which can mediate cellular iron uptake in vitro. Homozygous mutations of TfR2 cause haemochromatosis, suggesting that TfR2 alpha may not be a simple iron transporter, but a regulator of iron by identifying iron-Tf. In this study, we analysed the ligand specificity of TfR2 alpha using human transferrin receptor 1 (TfR1) and TfR2 alpha-stably transfected and expressing cells and flow-cytometric techniques. We showed that human TfR2 alpha interacted with both human and bovine Tf, whereas human TfR1 interacted only with human Tf. Neither human TfR1 nor TfR2 alpha interacted with either lactoferrin or melanotransferrin. In addition, by creating point mutations in human TfR2 alpha, the RGD sequence in the extracellular domain of TfR2 alpha was shown to be crucial for Tf-binding. Furthermore, we demonstrated that mutated TfR2 alpha (Y250X), which has been reported in patients with hereditary haemochromatosis, also lost its ability to interact with both human and bovine Tf. Although human TfR1 and TfR2 alpha share an essential structure (RGD) for ligand-binding, they have clearly different ligand specificities, which may be related to the differences in their roles in iron metabolism.
转铁蛋白受体2α（TfR2α）是TfR2基因的主要产物，是转铁蛋白（Tf）的第二种受体，其在体外可介导细胞对铁的摄取。TfR2的纯合突变会导致血色素沉着症，这表明TfR2α可能不是一个简单的铁转运蛋白，而是通过识别铁-Tf来调节铁的物质。在本研究中，我们使用人转铁蛋白受体1（TfR1）以及稳定转染并表达TfR2α的细胞和流式细胞术技术分析了TfR2α的配体特异性。我们发现人TfR2α与人及牛的Tf均有相互作用，而人TfR1仅与人Tf相互作用。人TfR1和TfR2α均不与乳铁蛋白或黑素转铁蛋白相互作用。此外，通过在人TfR2α中产生点突变，发现TfR2α胞外域中的RGD序列对于Tf结合至关重要。此外，我们证明了在遗传性血色素沉着症患者中报道的突变型TfR2α（Y250X）也失去了与人及牛Tf相互作用的能力。尽管人TfR1和TfR2α共享配体结合的基本结构（RGD），但它们具有明显不同的配体特异性，这可能与它们在铁代谢中的作用差异有关。
