Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Genes Dev. 2012 Feb 1;26(3):247-58. doi: 10.1101/gad.180885.111.
Synapses are the fundamental units of neural circuits that enable complex behaviors. The neuromuscular junction (NMJ), a synapse formed between a motoneuron and a muscle fiber, has contributed greatly to understanding of the general principles of synaptogenesis as well as of neuromuscular disorders. NMJ formation requires neural agrin, a motoneuron-derived protein, which interacts with LRP4 (low-density lipoprotein receptor-related protein 4) to activate the receptor tyrosine kinase MuSK (muscle-specific kinase). However, little is known of how signals are transduced from agrin to MuSK. Here, we present the first crystal structure of an agrin-LRP4 complex, consisting of two agrin-LRP4 heterodimers. Formation of the initial binary complex requires the z8 loop that is specifically present in neuronal, but not muscle, agrin and that promotes the synergistic formation of the tetramer through two additional interfaces. We show that the tetrameric complex is essential for neuronal agrin-induced acetylcholine receptor (AChR) clustering. Collectively, these results provide new insight into the agrin-LRP4-MuSK signaling cascade and NMJ formation and represent a novel mechanism for activation of receptor tyrosine kinases.
突触是神经回路的基本单位，使复杂行为成为可能。神经肌肉接头（NMJ）是运动神经元和肌肉纤维之间形成的突触，它对理解突触发生的一般原理以及神经肌肉疾病做出了巨大贡献。NMJ 的形成需要神经递质乙酰胆碱，一种运动神经元衍生的蛋白质，它与 LRP4（低密度脂蛋白受体相关蛋白 4）相互作用，激活受体酪氨酸激酶 MuSK（肌肉特异性激酶）。然而，关于信号如何从乙酰胆碱传递到 MuSK 的知之甚少。在这里，我们展示了第一个 agrin-LRP4 复合物的晶体结构，由两个 agrin-LRP4 异二聚体组成。初始二元复合物的形成需要 z8 环，该环仅存在于神经元而不存在于肌肉 agrin 中，并通过另外两个界面促进四聚体的协同形成。我们表明，四聚体复合物对于神经元 agrin 诱导的乙酰胆碱受体（AChR）聚集是必不可少的。总的来说，这些结果为 agrin-LRP4-MuSK 信号级联和 NMJ 形成提供了新的见解，并代表了激活受体酪氨酸激酶的新机制。
