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首页> 外文期刊>Journal of Molecular Biology >A single residue of GDF-5 defines binding specificity to BMP receptor IB
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A single residue of GDF-5 defines binding specificity to BMP receptor IB

机译：GDF-5的单个残基定义了与BMP受体IB的结合特异性

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Growth and differentiation factor 5 (GDF-5), a member of the TGF-beta superfamily, is involved in many developmental processes, like chondrogenesis and joint formation. Mutations in GDF-5 lead to diseases, e.g. chondrodysplasias like Hunter-Thompson, Grebe and DuPan syndromes and brachydactyly. Similar to other TGF-beta superfamily members, GDF-5 transmits signals through binding to two different types of membranebound serine-/threonine-kinase receptors termed type I and type II. In contrast to the large number of ligands, only seven type I and five type II receptors have been identified to date, implicating a limited promiscuity in ligand-receptor interaction. However, in contrast to other members of the TGF-beta superfamily, GDF-5 shows a pronounced specificity in type I receptor interaction in cross-link experiments binding only to BMP receptor IB (BMPR-IB). In mice, deletion of either GDF-5 or BMPR-IB results in a similar phenotype, indicating that GDF-5 signaling is highly dependent on BMPR-IB. Here, we demonstrate by biosensor analysis that GDF-5 also binds to BMP receptor IA (BMPR-IA) but with similar to 12-fold lower affinity. Structural and mutational analyses revealed a single residue of GDF-5, Arg57 located in the pre-helix loop, being solely responsible for the high binding specificity to BMPR-IB. In contrast to wild-type GDF-5, variant GDF-5R57A interacts with BMPR-IA and BMPR-IB with a comparable high binding affinity. These results provide important insights into how receptor-binding specificity is generated at the molecular level and might be useful for the generation of receptor subtype specific activators or inhibitors. (c) 2005 Elsevier Ltd. All rights reserved.
机译：TGF-β超家族成员之一生长和分化因子5（GDF-5）参与了许多发育过程，例如软骨形成和关节形成。 GDF-5突变会导致疾病，例如软骨发育不良，例如Hunter-Thompson，Grebe和DuPan综合征，以及近距离畸形。与其他TGF-β超家族成员相似，GDF-5通过与两种不同类型的膜结合的丝氨酸/苏氨酸激酶受体（称为I型和II型）结合而传输信号。与大量配体相反，迄今仅鉴定出七个I型和五个II型受体，这暗示了配体-受体相互作用的有限混杂性。但是，与TGF-β超家族的其他成员相反，GDF-5在仅与BMP受体IB（BMPR-IB）结合的交联实验中显示出I型受体相互作用的显着特异性。在小鼠中，GDF-5或BMPR-IB的缺失导致相似​​的表型，表明GDF-5信号高度依赖于BMPR-IB。在这里，我们通过生物传感器分析证明GDF-5也与BMP受体IA（BMPR-IA）结合，但亲和力低约12倍。结构和突变分析显示，GDF-5的单个残基位于螺旋前环中，这是对BMPR-IB的高结合特异性的唯一原因。与野生型GDF-5相反，变体GDF-5R57A以相当的高结合亲和力与BMPR-1A和BMPR-1B相互作用。这些结果提供了关于如何在分子水平上产生受体结合特异性的重要见解，并且可能对产生受体亚型特异性活化剂或抑制剂有用。 （c）2005 Elsevier Ltd.保留所有权利。

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