Stiegler Amy L, Burden Steven J, Hubbard Stevan R
Structural Biology Program, Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
J Mol Biol. 2009 Oct 16;393(1):1-9. doi: 10.1016/j.jmb.2009.07.091. Epub 2009 Aug 4.
Muscle-specific kinase (MuSK) is an essential receptor tyrosine kinase for the establishment and maintenance of the neuromuscular junction (NMJ). Activation of MuSK by agrin, a neuronally derived heparan-sulfate proteoglycan, and LRP4 (low-density lipoprotein receptor-related protein-4), the agrin receptor, leads to clustering of acetylcholine receptors on the postsynaptic side of the NMJ. The ectodomain of MuSK comprises three immunoglobulin-like domains and a cysteine-rich domain (Fz-CRD) related to those in Frizzled proteins, the receptors for Wnts. Here, we report the crystal structure of the MuSK Fz-CRD at 2.1 A resolution. The structure reveals a five-disulfide-bridged domain similar to CRDs of Frizzled proteins but with a divergent C-terminal region. An asymmetric dimer present in the crystal structure implicates surface hydrophobic residues that may function in homotypic or heterotypic interactions to mediate co-clustering of MuSK, rapsyn, and acetylcholine receptors at the NMJ.
肌肉特异性激酶（MuSK）是建立和维持神经肌肉接头（NMJ）所必需的受体酪氨酸激酶。神经源性硫酸乙酰肝素蛋白聚糖聚集蛋白以及聚集蛋白受体低密度脂蛋白受体相关蛋白4（LRP4）对MuSK的激活，会导致NMJ突触后侧乙酰胆碱受体的聚集。MuSK的胞外结构域包含三个免疫球蛋白样结构域和一个与Wnt受体卷曲蛋白中的结构域相关的富含半胱氨酸的结构域（Fz-CRD）。在此，我们报道了分辨率为2.1埃的MuSK Fz-CRD的晶体结构。该结构揭示了一个与卷曲蛋白的CRD相似但C端区域不同的五二硫键桥接结构域。晶体结构中存在的不对称二聚体表明，表面疏水残基可能在同型或异型相互作用中发挥作用，以介导MuSK、rapsyn和乙酰胆碱受体在NMJ处的共聚集。
