Structure of Myostatin.Follistatin-like 3 N-TERMINAL DOMAINS OF FOLLISTATIN-TYPE MOLECULES EXHIBIT ALTERNATE MODES OF BINDING
Structure of Myostatin.Follistatin-like 3 N-TERMINAL DOMAINS OF FOLLISTATIN-TYPE MOLECULES EXHIBIT ALTERNATE MODES OF BINDING
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DOI：
10.1074/jbc.m111.270801
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发表时间：
2012-01-06
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：
Cash, Jennifer N.;Angerman, Elizabeth B.;Thompson, Thomas B.
TGF-β家族配体参与多种关键生理过程。例如，TGF-β配体肌肉生长抑制素是肌肉生长的坚定负调节剂，也是肌肉萎缩性疾病的治疗靶点。因此，了解TGF-β家族调控的分子机制是非常重要的。调节的一种形式是通过细胞外拮抗剂如卵泡抑素（Fst）型蛋白的抑制。肌生长抑制素由Fst样3（Fst 13）严格控制，Fst样3是在血清中已鉴定的与肌生长抑制素结合的唯一Fst型分子。在这里，我们提出了与Fstl 3复合的肌肉生长抑制素的晶体结构。该结构揭示了与激活素A相比，Fstl 3的N-末端结构域（ND）独特地与肌生长抑制素相互作用，因为它利用配体上的不同表面。这导致Fstl 3的ND中的构象差异，其改变其在配体的I型受体结合位点中的位置。我们还表明，在ND的Fstl 3的单点突变是有害的配体结合，而相应的突变Fst几乎没有影响。总之，我们已经表明，ND的FST型分子表现出独特的配体结合模式，这可能会影响整体亲和力的配体。FST型蛋白质复合物。
TGF-beta family ligands are involved in a variety of critical physiological processes. For instance, the TGF-beta ligand myostatin is a staunch negative regulator of muscle growth and a therapeutic target for muscle-wasting disorders. Therefore, it is important to understand the molecular mechanisms of TGF-beta family regulation. One form of regulation is through inhibition by extracellular antagonists such as the follistatin (Fst)-type proteins. Myostatin is tightly controlled by Fst-like 3 (Fstl3), which is the only Fst-type molecule that has been identified in the serum bound to myostatin. Here, we present the crystal structure of myostatin in complex with Fstl3. The structure reveals that the N-terminal domain (ND) of Fstl3 interacts uniquely with myostatin as compared with activin A, because it utilizes different surfaces on the ligand. This results in conformational differences in the ND of Fstl3 that alter its position in the type I receptor-binding site of the ligand. We also show that single point mutations in the ND of Fstl3 are detrimental to ligand binding, whereas corresponding mutations in Fst have little effect. Overall, we have shown that the NDs of Fst-type molecules exhibit distinctive modes of ligand binding, which may affect overall affinity of ligand.Fst-type protein complexes.