Structural basis for agonism and antagonism of hepatocyte growth factor
Structural basis for agonism and antagonism of hepatocyte growth factor
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DOI：
10.1073/pnas.1005183107
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发表时间：
2010-07-27
影响因子：
11.1
通讯作者：
Xu, H. Eric
中科院分区：
文献类型：
--
作者：
Tolbert, W. David;Daugherty-Holtrop, Jennifer;Xu, H. Eric
肝细胞生长因子（HGF）是Met受体酪氨酸激酶的激活配体，其活性对正常组织发育和器官再生至关重要，但Met的异常激活与许多类型实体瘤的生长、侵袭和转移有关。HGF有两种天然剪接变体NK1和NK2，它们包含HGF的N端结构域(N)和第一kringle结构域（K1）或前两个kringle结构域。NK1是一种Met拮抗剂，在晶体结构中形成头尾二聚体复合物，NK1二聚体界面的突变将NK1转化为Met拮抗剂。而NK2是一种Met拮抗剂，能够抑制HGF在细胞增殖中的活性，但机制不明确。在这里，我们报道了NK2的晶体结构，它通过n域和第二kringle域（K2）之间的域间相互作用形成了一个“封闭”的单体构象。通过破坏N/K2界面来打开NK2封闭构象的突变将NK2从Met拮抗剂转变为激动剂。值得注意的是，这种突变的NK2激动剂可以通过破坏NK1/NK1二聚体界面的突变转化回拮抗剂。这些结果揭示了调控HGF NK2的激动剂/拮抗剂特性的分子决定因素，并为调控HGF激活Met受体的二聚化机制提供了重要的见解。
Hepatocyte growth factor (HGF) is an activating ligand of the Met receptor tyrosine kinase, whose activity is essential for normal tissue development and organ regeneration but abnormal activation of Met has been implicated in growth, invasion, and metastasis of many types of solid tumors. HGF has two natural splice variants, NK1 and NK2, which contain the N-terminal domain (N) and the first kringle (K1) or the first two kringle domains of HGF. NK1, which is a Met agonist, forms a head-to-tail dimer complex in crystal structures and mutations in the NK1 dimer interface convert NK1 to a Met antagonist. In contrast, NK2 is a Met antagonist, capable of inhibiting HGF's activity in cell proliferation without clear mechanism. Here we report the crystal structure of NK2, which forms a "closed" monomeric conformation through interdomain interactions between the N-domain and the second kringle domain (K2). Mutations that were designed to open up the NK2 closed conformation by disrupting the N/K2 interface convert NK2 from a Met antagonist to an agonist. Remarkably, this mutated NK2 agonist can be converted back to an antagonist by a mutation that disrupts the NK1/NK1 dimer interface. These results reveal the molecular determinants that regulate the agonist/antagonist properties of HGF NK2 and provide critical insights into the dimerization mechanism that regulates the Met receptor activation by HGF.