特发性癫痫蛋白LGI1与受体ADAMs复合物的结构生物学研究

Afflicting approximately 1-2 in 100 individuals around the world, epilepsy is one of the most common neurological disorders. In China, about 9 million people are suffering from such a devastating and poorly understood disease.The channelopathy concept for idiopathic epilepsies has been prevalent since human genetic studies have revealed that many of the genes whose mutations cause epilepsy encode ion channels.LGI1 (Leucine-rich glioma inactivated 1) is a unique idiopathic epilepsy predisposition gene, because it encodes a neuronal secreted protein, rather than an ion channel. Accumulating evidence has confirmed that mutations of LGI1 are directly linked to autosomal dominant lateral temporal lobe epilepsy (ADLTE), which is an idiopathic epilepsy characterized by partial seizures with acoustic aura. Through binding to its receptors ADAM22/ADAM23（ADAMs） on synaptic membranes, LGI1 acts as an antiepileptogenic ligand that has an essential role of inhibiting epileptogenesis. However, how LGI1 recognizes its receptors remains unclear, and the mechanisms underlying how ADLTE-related mutations of LGI1 lead to epileptogenesis through dysfunction of ligand-receptor complexes are highly controversial.In this proposal, the applicant plans to perform structural biology study on the complexes between LGI1 and its receptors. One aim of the proposed project is to elucidate the structural basis of ligand-receptor interaction; the other one is, based on the structural basis, to investigate the pathological mechanisms of LGI1 mutations at molecular, cellular and circuit levels.Even though both LGI1 and ADAM22 are glycosylated proteins that are not easily accessible for crystallization, the applicant has already determined crystal structure of ADAM22 and has gained crystals of the LGI1-ADAM22 complex, which suggests that the proposed project is doable. Since LGI1 is a unique epilepsy-related gene, the proposed project will offer new insights into pathological basis of epilepsy, and for development of new anti-epilepsy drugs.

富亮氨酸胶质瘤失活基因-1（LGI1）的突变与常染色体显性遗传颞叶外侧癫痫直接相关。大多数特发性癫痫致病基因编码离子通道，而LGI1编码分泌型富亮氨酸胶质瘤失活蛋白-1。该蛋白通过作用于突触前后膜上的受体ADAM22/ADAM23(ADAMs)而具有抑制癫痫发生的功能，为此，被称作抗癫痫配体。但LG1如何识别受体、LGI1突变如何影响它与受体的复合物的功能从而引发癫痫等问题一直悬而未决。申请人拟开展关于LGI1-ADAMs复合物的结构生物学研究，试图阐明配体-受体相互作用的结构机制，并以复合物结构为基础，在分子、细胞、回路三个层次上说明LGI1突变的分子致病机理。虽然LGI1和ADAM22是不易结晶的糖蛋白，但申请人已经获得ADAM22的晶体结构以及LGI1-ADAM22复合物的晶体，这表明了项目的可行性。鉴于LGI1的独特性，本项目可为癫痫发病机制研究和抗癫痫药物开发提供新视角。