Turk Liam S, Kuang Xuyuan, Dal Pozzo Valentina, Patel Khush, Chen Muyuan, Huynh Kevin, Currie Michael J, Mitchell Daniel, Dobson Renwick C J, D'Arcangelo Gabriella, Dai Wei, Comoletti Davide
Child Health Institute of New Jersey, New Brunswick, NJ 08901, USA; Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA; School of Biological Sciences, Victoria University of Wellington, Wellington 6012, New Zealand.
Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Hyperbaric Oxygen, Central South University, Changsha, Hunan Province, China.
Structure. 2021 Oct 7;29(10):1156-1170.e6. doi: 10.1016/j.str.2021.05.012. Epub 2021 Jun 4.
Reelin operates through canonical and non-canonical pathways that mediate several aspects of brain development and function. Reelin's dimeric central fragment (CF), generated through proteolytic cleavage, is required for the lipoprotein-receptor-dependent canonical pathway activation. Here, we analyze the signaling properties of a variety of Reelin fragments and measure the differential binding affinities of monomeric and dimeric CF fragments to lipoprotein receptors to investigate the mode of canonical signal activation. We also present the cryoelectron tomography-solved dimeric structure of Reelin CF and support it using several other biophysical techniques. Our findings suggest that Reelin CF forms a covalent parallel dimer with some degree of flexibility between the two protein chains. As a result of this conformation, Reelin binds to lipoprotein receptors in a manner inaccessible to its monomeric form and is capable of stimulating canonical pathway signaling.
Reelin通过经典和非经典途径发挥作用，这些途径介导大脑发育和功能的多个方面。通过蛋白水解切割产生的Reelin二聚体中央片段（CF）是脂蛋白受体依赖性经典途径激活所必需的。在这里，我们分析了多种Reelin片段的信号特性，并测量了单体和二聚体CF片段与脂蛋白受体的差异结合亲和力，以研究经典信号激活模式。我们还展示了通过冷冻电子断层扫描解析的Reelin CF二聚体结构，并使用其他几种生物物理技术进行了支持。我们的研究结果表明，Reelin CF形成了一个共价平行二聚体，两条蛋白质链之间具有一定程度的灵活性。由于这种构象，Reelin以其单体形式无法接近的方式与脂蛋白受体结合，并能够刺激经典途径信号传导。
