Elucidating the structural insights into the BMP receptor mutations in PAH

项目摘要/摘要 肺动脉高压(PAH)是一种进行性疾病，如果不治疗会导致3年内死亡。多环芳烃 以肺动脉重塑和最终闭塞为特征，随后是高PA压。 还有右心衰竭。骨形态发生蛋白受体2型基因杂合性突变 是PAH的主要遗传原因。在带有BMPR2突变的患者中，PAH发生的时间提前了数年，而在 更严重的形式，比正常的BMPR2患者。尽管最近在识别 BMPR2突变的分子和细胞后果，也没有针对BMPR2携带者的靶向治疗 对新疗法的迫切需求已经得到满足。 BMP信号的良好支持模型始于配体与一组跨膜 丝氨酸/苏氨酸受体激酶由两个1型受体(BMRPI)和两个2型受体(BMPR2)组成。 异四聚体活性BMP受体复合体使携带信号的Smad蛋白磷酸化 向下延伸到原子核。这一模型的不足之处包括缺乏对为什么受体需要 以异四聚体构型组织成活性，以及受体激酶是如何被激活的。 因此，我们对定位于BMPR2细胞内区域的流行多环芳烃突变的理解 仍然不令人满意，禁止推进多环芳烃的靶向治疗。我们最近的研究导致了一个 发现BMPR2的激动域与1型BMP受体激酶形成异二聚体。形成 异源二聚体不足以激活1型激酶，但对于配体诱导的受体信号转导是必不可少的。 提示它在活性受体四聚体的组装中起重要作用。重要的是，几个BMPR2突变体 连接到PAH映射到异二聚体界面并抑制配体诱导的下游Smad信号， 支持异源二聚体界面的生理意义。这个应用程序的目标是阐明 骨形态发生蛋白受体激酶激活的分子基础并阐明对BMPR2的了解如何 突变通过以下方式触发PAH：(I)解剖1型/1型激酶寡聚在催化反应中的作用 BMP受体复合体的激活、下游信号传递和血管内稳态，以及(Ii)获得 对活性的1/2激活型结构域复合体的结构理解 长度BMP受体四聚体。完成后，这项研究将确定非催化的意义 BMP受体激酶上存在的界面，为了解BMPR2突变如何扰乱该类型提供了洞察力 1/2型激酶相互作用导致PAH。这些知识将为发展提供平台 创新的PAH疗法。

PROJECT SUMMARY/ABSTRACT Pulmonary Arterial Hypertension (PAH) is a progressive disease that leads to death in 3 years if untreated. PAH is characterized by remodeling and eventually occlusion of the pulmonary arteries, followed by high PA pressure and right heart failure. Heterozygous mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2) are the leading genetic cause of PAH. In patients with BMPR2 mutations, PAH develops years earlier, and in a more severe form, than in patients with normal BMPR2. Notwithstanding the recent progress in identifying the molecular and cellular consequences of BMPR2 mutations, no targeted therapy for BMPR2 carriers exist, nor the dire need for novel therapies has been met. A well-supported model of BMP signaling starts with a ligand binding to a group of transmembrane serine/threonine receptor kinases comprised of two type 1 receptor (BMRPI) and two type 2 receptors (BMPR2). The heterotetrameric active BMP receptor complex phosphorylates Smad proteins that carry the signal downstream to the nucleus. Gaps in this model include lack of understanding why the receptors need to be organized in a heterotetramer configuration to be active, and how the receptor kinases are activated. Consequently, our understanding of prevalent PAH mutations that localize to the BMPR2 intracellular regions remains unsatisfactory and prohibitive from advancing PAH-targeted therapies. Our recent studies have led to a discovery that kinase domain of BMPR2 forms a heterodimer with a type 1 BMP receptor kinase. Formation of the heterodimer is not sufficient to activate the type 1 kinase but is essential for ligand-induced receptor signaling, suggesting its essential role in assembly of the active receptor tetramer. Importantly, several BMPR2 mutants linked to PAH map to the heterodimer interface and inhibit ligand-induced downstream Smad signaling, supporting the physiological significance of the heterodimer interface. The goal of this application is to elucidate the molecular underpinnings of BMP receptor kinase activation and elucidate how poorly understood BMPR2 mutations trigger PAH by: (i) dissecting the role of the type 1/type 1 kinase oligomerization in the catalytic activation of the BMP receptor complex, downstream signaling, and vascular homeostasis, and (ii) gaining the structural understanding of the active type 1/type 2 kinase domain complexes alone and in the context of full- length BMP receptor tetramers. Upon completion, this study will define the significance of the non-catalytic interfaces present on BMP receptor kinases and provide insights into how BMPR2 mutations perturb the type 1/type 2 kinase interactions resulting in PAH. This knowledge will provide platform for the development of innovative novel PAH therapies.