Journal
STRUCTURE
Volume 10, Issue 9, Pages 1187-1196Publisher
CELL PRESS
DOI: 10.1016/S0969-2126(02)00814-6
Keywords
tyrosine kinase; crystal structure; phosphorylation; signal transduction; mass spectrometry; neuromuscular junction
Funding
- NCRR NIH HHS [RR14662] Funding Source: Medline
- NIDDK NIH HHS [DK52916] Funding Source: Medline
- NINDS NIH HHS [R01 NS036193, NS41311, R01 NS036193-05, NS36193] Funding Source: Medline
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Muscle-specific kinase (MuSK) is a receptor tyrosine kinase expressed selectively in skeletal muscle. During neuromuscular synapse formation, agrin released from motor neurons stimulates MuSK autophosphorylation in the kinase activation loop and in the juxtamembrane region, leading to clustering of acetylcholine receptors. We have determined the crystal structure of the cytoplasmic domain of unphosphorylated MuSK at 2.05 Angstrom resolution. The structure reveals an autoinhibited kinase domain in which the activation loop obstructs ATP and substrate binding. Steady-state kinetic analysis demonstrates that autophosphorylation results in a 200-fold increase in k(cat) and a 10-fold decrease in the K-m for ATP. These studies provide a molecular basis for understanding the regulation of MuSK catalytic activity and suggest that an additional in vivo component may contribute to regulation via the juxtamembrane region.
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