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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要肺动脉高压 (PAH) 是一种进行性疾病，如果不治疗，会在 3 年内导致死亡。多环芳烃其特点是肺动脉重塑并最终闭塞，随后出现高 PA 压力和右心衰竭。骨形态发生蛋白受体 2 型基因 (BMPR2) 杂合突变是 PAH 的主要原因。在具有 BMPR2 突变的患者中，多环芳烃 (PAH) 会提前数年出现，并且比 BMPR2 正常的患者更严重。尽管最近在确定 BMPR2 突变的分子和细胞后果，不存在针对 BMPR2 携带者的靶向治疗，也不存在对新疗法的迫切需求已经得到满足。得到充分支持的 BMP 信号传导模型始于配体与一组跨膜结合丝氨酸/苏氨酸受体激酶由两种 1 型受体 (BMRPI) 和两种 2 型受体 (BMPR2) 组成。异四聚体活性 BMP 受体复合物磷酸化携带信号的 Smad 蛋白下游至细胞核。该模型中的缺陷包括缺乏理解为什么受体需要被以异四聚体构型组织起来具有活性，以及受体激酶如何被激活。因此，我们对位于 BMPR2 细胞内区域的常见 PAH 突变的理解仍然不能令人满意并且阻碍了 PAH 靶向治疗的进展。我们最近的研究导致了发现 BMPR2 的激酶结构域与 1 型 BMP 受体激酶形成异二聚体。的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传导至关重要，表明其在活性受体四聚体的组装中发挥重要作用。重要的是，一些 BMPR2 突变体与 PAH 映射到异二聚体界面相关并抑制配体诱导的下游 Smad 信号传导，支持异二聚体界面的生理意义。该应用程序的目标是阐明 BMP 受体激酶激活的分子基础并阐明人们对 BMPR2 知之甚少突变通过以下方式触发 PAH：(i) 剖析 1 型/1 型激酶寡聚化在催化中的作用 BMP 受体复合物的激活、下游信号传导和血管稳态，以及 (ii) 获得单独和在完整的背景下对活性 1 型/2 型激酶结构域复合物的结构理解 BMP受体四聚体的长度。完成后，这项研究将定义非催化的重要性 BMP 受体激酶上存在的界面并提供有关 BMPR2 突变如何扰乱类型的见解 1/2 型激酶相互作用导致 PAH。这些知识将为我们的发展提供平台创新的新型 PAH 疗法。