Another RTK of interest is MuSK, or muscle-specific kinase, which is expressed exclusively in muscle cells and plays an essential role in the formation of neuromuscular synapses by promoting clustering of acetylcholine receptors. Activation of MuSK by agrin results in autophosphorylation of several tyrosines in the cytoplasmic domain of MuSK. In a collaboration with Dr. Steven Burden at the Skirball Institute (NYU School of Medicine), we have determined the crystal structure of the cytoplasmic (tyrosine kinase-containing) domain of MuSK to understand how kinase activity is regulated in this receptor. The structure reveals that MuSK is strongly autoinhibited by the kinase activation loop.

In addition to determining the crystal structure of the tyrosine kinase domain of MuSK, we have determined crystal structures of the first two immunoglobulin-like domains (Ig1-2) and the Frizzled-like cysteine-rich domain (Fz-CRD) of the MuSK extracellular region. Ig1-2 crystallized as a dimer, mediated by Ig1, and the residues in the dimer interface are critical for agrin-induced phosphorylation of the receptor. Whether these residues are important for receptor dimerization or for a heterologous interaction (e.g., with the agrin receptor, LRP4) is still under investigation.


Molecular surface representation of dimeric Ig1-2 of the MuSK ectodomain. Ig1 is colored light green/purple, and Ig2 is colored dark green/purple. The dimer interface is mediated solely by residues in Ig1. [Stiegler et al., J. Mol. Biol. 364, 424-433 (2006)]

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Ribbon diagram of the Fz-CRD of MuSK. The disulfide bridges are shown in ball-and-stick representation with sulfur atoms colored yellow and carbon atoms colored gray. [Stiegler et al., J. Mol. Biol. 393, 1-9 (2009)]

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