School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Interdisciplinary Institute of NMR and Molecular Sciences, School of Chemistry and Chemical Engineering, The State Key Laboratory of Refractories and Metallurgy, Wuhan University of Science and Technology, Wuhan, 430081, China.
Nat Commun. 2024 Aug 14;15(1):6975. doi: 10.1038/s41467-024-51303-y.
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.
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 具有三个不同的功能域，中心域包含一个受体相互作用蛋白同源相互作用基序（RHIM），介导淀粉样形成。由 RIPK1 和/或 RIPK3 形成的功能性淀粉样蛋白是调节细胞坏死性细胞死亡的关键中间物。在这项研究中，展示了由 RHIM 为中心的 82 个残基序列形成的小鼠 RIPK1 的淀粉样结构。它揭示了纤维状蛋白亚基的“N”形折叠，其中包含四个β-链。这种折叠模式与具有 RHIM 的几种蛋白质形成的淀粉样结构共享，其中由最保守的四联体序列 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 之间存在结构差异。通过观察到在与 RIPK1 混合形成 RIPK1/RIPK3 复合物纤维时，小鼠 RIPK3 的信号减弱，也表明结构刚性发生了变化。我们的结果为理解具有 RHIM 的不同蛋白质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细胞死亡的调节机制。
