PDF(Pubmed)
Abstract：
Receptor-interacting protein kinase 1 (RIPK1) is a therapeutic target in treating neurodegenerative diseases and cancers. RIPK1 has three distinct functional domains, with the center domain containing a receptor-interacting protein homotypic interaction motif (RHIM), which mediates amyloid formation. The functional amyloid formed by RIPK1 and/or RIPK3 is a crucial intermediate in regulating cell necroptosis. In this study, the amyloid structure of mouse RIPK1, formed by an 82-residue sequence centered at RHIM, is presented. It reveals the \"N\"-shaped folding of the protein subunit in the fibril with four β-strands. The folding pattern is shared by several amyloid structures formed by proteins with RHIM, with the central β-strand formed by the most conserved tetrad sequence I/VQI/VG. However, the solid-state NMR results indicate a structural difference between mouse RIPK1 and mouse RIPK3. A change in the structural rigidity is also suggested by the observation of weakened signals for mouse RIPK3 upon mixing with RIPK1 to form the RIPK1/RIPK3 complex fibrils. Our results provide vital information to understand the interactions between different proteins with RHIM, which will help us further comprehend the regulation mechanism in cell necroptosis.
摘要：
受体相互作用蛋白激酶1（RIPK1）是治疗神经退行性疾病和癌症的治疗靶点。RIPK1有三个不同的功能结构域，中心域包含受体相互作用蛋白同型相互作用基序（RHIM），介导淀粉样蛋白的形成。由RIPK1和/或RIPK3形成的功能性淀粉样蛋白是调节细胞坏死性凋亡的关键中间体。在这项研究中,小鼠RIPK1的淀粉样蛋白结构，由一个以RHIM为中心的82个残基的序列形成，是presented。它揭示了原纤维中蛋白质亚基的“N”形折叠，具有四个β链。折叠模式由蛋白质与RHIM形成的几种淀粉样结构共享，由最保守的四聚体序列I/VQI/VG形成的中央β链。然而,固态NMR结果表明小鼠RIPK1和小鼠RIPK3之间的结构差异。通过与RIPK1混合形成RIPK1/RIPK3复合原纤维后观察到小鼠RIPK3的减弱信号，也表明了结构刚度的变化。我们的结果为了解不同蛋白质与RHIM之间的相互作用提供了重要信息，这将有助于我们进一步理解细胞坏死性凋亡的调控机制。
