Crystal structure of the agrin-responsive immunoglobulin-like domains 1 and 2 of the receptor tyrosine kinase MuSK

JOURNAL OF MOLECULAR BIOLOGY

卷:364

Article

Stiegler, Amy L. ; Burden, Steven J. ; Hubbard, Stevan R.

关键词: agrin;    crystal structure;    MuSK;    neuromuscular junction;    receptor tyrosine kinase;   

DOI  :  10.1016/j.jmb.2006.09.019

来源: Elsevier

【 摘 要 】

Muscle-specific kinase (MuSK) is a receptor tyrosine kinase expressed exclusively in skeletal muscle, where it is required for formation of the neuromuscular junction. MuSK is activated by agrin, a neuron-derived heparan sulfate proteoglycan. Here, we report the crystal structure of the agrin-responsive first and second immunoglobulin-like domains (Ig1 and Ig2) of the MuSK ectodomain at 2.2 angstrom resolution. The structure reveals that MuSK IgI and Ig2 are Ig-like domains of the I-set subfamily, which are configured in a linear, semi-rigid arrangement. In addition to the canonical internal disulfide bridge, Ig1 contains a second, solvent-exposed disulfide bridge, which our biochemical data indicate is critical for proper folding of IgI and processing of MuSK. Two Ig1-2 molecules form a non-crystallographic dimer that is mediated by a unique hydrophobic patch on the surface of Ig1. Biochemical analyses of MuSK mutants introduced into MuSK(-/-) myotubes demonstrate that residues in this hydrophobic patch are critical for agrin-induced MuSK activation. (c) 2006 Elsevier Ltd. All rights reserved.

【 授权许可】

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