The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH-dependent binding to albumin
The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH-dependent binding to albumin
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DOI：
10.1002/eji.200636556
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发表时间：
2006-11-01
影响因子：
5.4
通讯作者：
Sandlie, Inger
中科院分区：
文献类型：
--
作者：
Andersen, Jan Terje;Qian, Julie Dee;Sandlie, Inger
MHC I类相关的新生儿Fc受体（FcRn）通过增加IgG和白蛋白的半衰期，在体内平衡调节中发挥作用。FcRn可以同时结合IgG和白蛋白，并且以pH依赖性方式，在pH 6.0-6.5下结合配体，在pH 7.0-7.4下释放。已在氨基酸水平上对FcRn-IgG相互作用进行了广泛表征，并显示其依赖于IgG-Fc部分中与FcRn α-2结构域中带负电荷残基相互作用的保守组氨酸残基。最近发现的FcRn-白蛋白相互作用仍有待阐明。在FcRn-白蛋白相互作用的pH依赖性的指导下，我们比较了11个不同物种的FcRn α-2结构域的序列，并鉴定了其中所有（H166）或七个（H161）中保守的组氨酸残基。两个残基都位于折叠分子中IgG相互作用位点的正对面。我们进行了体外诱变（H161 A或H166 A）与重组，可溶性，纯化的受体和IgG和白蛋白的相互作用研究（ELISA和表面等离子体共振）相结合，以研究两个组氨酸残基的作用。我们的研究结果表明，保守的H166是一个关键的球员在FcRn-白蛋白的相互作用。
The MHC class I-related neonatal Fc receptor (FcRn) serves in the homeostatic regulation of IgG and albumin by increasing their half-lives. FcRn may bind IgG and albumin simultaneously, and in a pH-dependent manner, with ligand binding at pH 6.0-6.5 and release at pH 7.0-7.4. The FcRn-IgG interaction has been extensively characterized at the amino acid level and shown to depend on conserved histidine residues in the IgG-Fc part that interact with negatively charged residues in the alpha-2 domain of FcRn. The recently discovered FcRn-albumin interaction remains to be elucidated. Guided by the pH dependence of the FcRn-albumin interaction, we compared the sequence of the FcRn alpha-2 domain from eleven different species, and identified histidine residues that were conserved in all (H166) or seven (H161) of these. Both residues are located directly opposite to the IgG interaction site in the folded molecule. We did in vitro mutagenesis (H161A or H166A) in combination with interaction studies (ELISA and surface plasmon resonance) with recombinant, soluble, purified receptors and IgG and albumin to investigate the role of the two histidine residues. Our results show clear evidence that the conserved H166 is a key player in the FcRn-albumin interaction.