Structural insights into the assembly of the agrin/LRP4/MuSK signaling complex

Proc Natl Acad Sci U S A. 2023 Jun 6;120(23):e2300453120. doi: 10.1073/pnas.2300453120. Epub 2023 May 30.

Abstract

MuSK is a receptor tyrosine kinase (RTK) that plays essential roles in the formation and maintenance of the neuromuscular junction. Distinct from most members of RTK family, MuSK activation requires not only its cognate ligand agrin but also its coreceptors LRP4. However, how agrin and LRP4 coactivate MuSK remains unclear. Here, we report the cryo-EM structure of the extracellular ternary complex of agrin/LRP4/MuSK in a stoichiometry of 1:1:1. This structure reveals that arc-shaped LRP4 simultaneously recruits both agrin and MuSK to its central cavity, thereby promoting a direct interaction between agrin and MuSK. Our cryo-EM analyses therefore uncover the assembly mechanism of agrin/LRP4/MuSK signaling complex and reveal how MuSK receptor is activated by concurrent binding of agrin and LRP4.

Keywords: LRP4; MuSK; NMJ; RTK; agrin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agrin* / chemistry
  • Agrin* / metabolism
  • LDL-Receptor Related Proteins / chemistry
  • Neuromuscular Junction / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Cholinergic* / metabolism
  • Signal Transduction

Substances

  • Receptors, Cholinergic
  • Agrin
  • LDL-Receptor Related Proteins
  • Receptor Protein-Tyrosine Kinases