title: Crystal structure of the MuSK tyrosine kinase: insights into receptor autoregulation.
abstract: 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 A 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.
authors.affiliation: Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York university School of Medicine, New York, NY 10016, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Till
authors.forename: Manuel
authors.initials: M
authors.lastname: Becerra
authors.forename: Anke
authors.initials: A
authors.lastname: Watty
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Ma
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neubert
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burden
authors.forename: Stevan R
authors.initials: SR
authors.lastname: Hubbard
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D007700:Kinetics; D013058:Mass Spectrometry; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D011950:Receptors, Cholinergic; C095714:MUSK protein, human; C475048:MuSK protein, rat; D020794:Receptor Protein-Tyrosine Kinases