A single residue of GDF-5 defines binding specificity to BMP receptor IB
A single residue of GDF-5 defines binding specificity to BMP receptor IB
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DOI：
10.1016/j.jmb.2005.04.015
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发表时间：
2005-06-24
影响因子：
5.6
通讯作者：
Mueller, TD
中科院分区：
文献类型：
--
作者：
Nickel, J;Kotzsch, A;Mueller, TD
生长和分化因子5（GDF-5）是TGF-β超家族的成员，参与许多发育过程，如软骨形成和关节形成。GDF-5中的突变导致疾病，例如软骨发育不良如Hunter-Thompson、Grebe和DuPan综合征和短指（趾）畸形。与其他TGF-β超家族成员类似，GDF-5通过与两种不同类型的膜结合丝氨酸/苏氨酸激酶受体（称为I型和II型）结合来传递信号。与大量的配体相反，迄今为止仅鉴定出7种I型和5种II型受体，这暗示了配体-受体相互作用中的有限混杂性。然而，与TGF-β超家族的其他成员相比，GDF-5在仅结合BMP受体IB（BMPR-IB）的交联实验中显示出I型受体相互作用的显著特异性。在小鼠中，GDF-5或BMPR-IB的缺失导致相似的表型，表明GDF-5信号传导高度依赖于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12倍。结构和突变分析揭示了位于螺旋前环的GDF-5的单个残基Arg 57，其单独负责与BMPR-IB的高结合特异性。与野生型GDF-5相反，变体GDF-5 R57 A以相当高的结合亲和力与BMPR-IA和BMPR-IB相互作用。这些结果提供了重要的见解如何受体结合特异性产生在分子水平上，并可能是有用的受体亚型特异性激活剂或抑制剂的产生。(c)2005 Elsevier Ltd.保留所有权利。
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.