Mutational Analysis of the Putative Anti-Mullerian Hormone (AMH) Binding Interface on its Type II Receptor, AMHR2
Mutational Analysis of the Putative Anti-Mullerian Hormone (AMH) Binding Interface on its Type II Receptor, AMHR2
复制标题
抗苗勒管激素（AMH） II型受体AMHR2结合界面的突变分析
DOI：
10.1210/endocr/bqaa066
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发表时间：
2020-07-01
期刊：
影响因子：
4.8
通讯作者：
Thompson, Thomas B.
中科院分区：
文献类型：
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作者：
Hart, Kaitlin N.;Pepin, David;Thompson, Thomas B.
抗苗勒管激素 (AMH) 或苗勒管抑制物质是 TGF-β 家族的独特成员，负责生殖系统的发育和分化。 AMH 通过其专用的 II 型受体（AMHR2）发出信号，在更广泛的 TGF-β 家族中提供独特的配体-受体对。在这项研究中，我们利用之前的结构信息推导了与 AMHR2 结合的 AMH 模型，以指导诱变研究，以确定对 AMH 信号传导重要的受体残基。在 AMHR2 中引入非保守突变，并通过基于 AMH 响应的细胞荧光素酶测定和天然 PAGE 进行表征。总的来说，我们的结果确定了 AMHR2 假定配体结合界面内对 AMH 信号传导重要的几个残基。我们的结果表明，AMH 与 AMHR2 的结合界面与激活素和 BMP 类配体结合 II 型受体 ACVR2B 的界面相似；然而，这两种受体的配体界面存在显着的分子差异，其中 ACVR2B 主要是疏水性的，而 AMHR2 主要是带电荷的。总体而言，本研究表明，虽然配体结合在受体上的位置与ACVR2A、ACVR2B和BMPR2相似； AMHR2 使用独特的配体-受体相互作用来赋予 AMH 特异性。
Anti-Mullerian hormone (AMH) or Mullerian inhibiting substance is a unique member of the TGF-beta family responsible for development and differentiation of the reproductive system. AMH signals through its own dedicated type II receptor, anti-Mullerian hormone receptor type II (AMHR2), providing an exclusive ligand-receptor pair within the broader TGF-beta family. In this study, we used previous structural information to derive a model of AMH bound to AMHR2 to guide mutagenesis studies to identify receptor residues important for AMH signaling. Nonconserved mutations were introduced in AMHR2 and characterized in an AMH-responsive cell-based luciferase assay and native PAGE. Collectively, our results identified several residues important for AMH signaling within the putative ligand binding interface of AMHR2. Our results show that AMH engages AMHR2 at a similar interface to how activin and BMP class ligands bind the type II receptor, ACVR2B; however, there are significant molecular differences at the ligand interface of these 2 receptors, where ACVR2B is mostly hydrophobic and AMHR2 is predominately charged. Overall, this study shows that although the location of ligand binding on the receptor is similar to ACVR2A, ACVR2B, and BMPR2; AMHR2 uses unique ligand-receptor interactions to impart specificity for AMH.