Elucidating the structural insights into the BMP receptor mutations in PAH

阐明 PAH 中 BMP 受体突变的结构见解

• 批准号: 10659947
• 负责人: Akiko Hata
• 金额: $ 80.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659947
• 关键词: ACVR1 gene; ACVRL1 gene; Activin Receptor; BMP2 gene; Binding; Biological Assay; Biophysics; Blood Vessels; Bone Morphogenetic Protein Receptor Gene; C-terminal; Catalytic Domain; Cell Nucleus; Cells; Cessation of life; Complex; Cryoelectron Microscopy; Deuterium; Development; Disease; Distal; Family; Gene Mutation; Gene Structure; Genes; Genetic; Goals; Heritability; Heterozygote; Homeostasis; Hydrogen; In Vitro; Investigation; Knowledge; Length; Ligand Binding; Ligand Binding Domain; Ligands; Light; Link; Lung; Maintenance; Maps; Mass Spectrum Analysis; Measures; Membrane; Membrane Biology; Methods; Modeling; Molecular; Molecular Conformation; Morbidity - disease rate; Mutagenesis; Mutation; Pathogenesis; Pathogenicity; Pathologic; Patients; Phosphorylation; Phosphotransferases; Physiological; Progressive Disease; Pulmonary arterial remodeling; Pulmonary artery structure; Receptor Activation; Receptor Gene; Receptor Serine/Threonine Kinase; Receptor Signaling; Regulation; Research; Rodent; Roentgen Rays; Role; Signal Pathway; Signal Transduction; Site; Smad Proteins; Structural Models; Structure; Tail; Time; Transforming Growth Factor beta; Transmembrane Domain; Variant; Vascular Diseases; Vascular Endothelial Cell; Work; X-Ray Crystallography; activin receptor-like kinase 1; bone morphogenetic protein receptors; extracellular; innovation; insight; interdisciplinary approach; lung microvascular endothelial cells; member; mortality; mutant; novel; novel therapeutics; primary pulmonary hypertension; pulmonary arterial hypertension; pulmonary arterial pressure; receptor; reconstitution; right ventricular failure; stem; structural biology; success; targeted treatment

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.

项目摘要/摘要 肺动脉高压（PAH）是一种进行性疾病，如果未治疗，在3年内导致死亡。 pah 其特征是重塑和最终阻塞肺动脉，然后是高PA压力 和正确的心力衰竭。骨形态发生蛋白受体2型基因中的杂合突变（BMPR2） 是PAH的主要遗传原因。在BMPR2突变的患者中，PAH在几年前成长，在 比正常BMPR2患者更严重。尽管最近取得了确定的进展 BMPR2突变的分子和细胞后果，不存在针对BMPR2载体的靶向治疗，也不存在 已经满足了新型疗法的可怕需求。 BMP信号的良好支撑模型始于配体与一组跨膜的结合 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。 杂型型活性BMP受体复合物磷酸化携带信号的Smad蛋白 下游到核。该模型中的差距包括缺乏了解受体为什么需要的理解 在异驱动型构型中组织以具有活性，以及​​如何激活受体激酶。 因此，我们对位于BMPR2细胞内区域的普遍PAH突变的理解 推进靶向PAH的疗法仍然不令人满意和刺激性。我们最近的研究导致了 发现BMPR2的激酶结构域形成具有1型BMP受体激酶的异二聚体。形成 异二聚体不足以激活1型激酶，但对于配体诱导的受体信号至关重要， 表明其在主动受体四聚体组装中的重要作用。重要的是，几个BMPR2突变体 链接到PAH地图与异二聚体界面并抑制配体诱导的下游SMAD信号， 支持异二聚体界面的生理意义。此应用的目的是阐明 BMP受体激酶激活的分子基础，并阐明了BMPR2的理解较差 突变触发PAH：（i）剖析催化中1/类型1激酶寡聚的作用 BMP受体复合物，下游信号传导和血管稳态的激活，以及（ii）获得 单独和在全面的背景下，对活性1/类型2激酶结构域复合物的结构理解 长度BMP受体四聚体。完成后，本研究将定义非催化的重要性 BMP受体激酶上存在的接口，并提供有关BMPR2突变如何扰动类型的见解 1/2型激酶相互作用导致PAH。这些知识将为开发的平台提供平台 创新的小说PAH疗法。