Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 364, Issue 3, Pages 424-433Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2006.09.019
Keywords
agrin; crystal structure; MuSK; neuromuscular junction; receptor tyrosine kinase
Categories
Funding
- NINDS NIH HHS [R01 NS053414, R01 NS036193-09, R37 NS036193, NS053414, R01 NS036193, NS036193] Funding Source: Medline
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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.
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