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

J Mol Biol. 2006 Dec 1;364(3):424-33. doi: 10.1016/j.jmb.2006.09.019. Epub 2006 Sep 12.

Abstract

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 A resolution. The structure reveals that MuSK Ig1 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 Ig1 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Agrin / chemistry*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Line
  • Immunoglobulins / chemistry*
  • Models, Molecular*
  • Molecular Sequence Data
  • Mutation
  • Protein Folding
  • Protein Structure, Tertiary
  • Rats
  • Receptor Protein-Tyrosine Kinases / chemistry*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptors, Cholinergic / chemistry*
  • Receptors, Cholinergic / genetics
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics

Substances

  • Agrin
  • Immunoglobulins
  • Receptors, Cholinergic
  • Recombinant Proteins
  • MuSK protein, rat
  • Receptor Protein-Tyrosine Kinases

Associated data

  • PDB/2IEP