Structural basis of agrin-LRP4-MuSK signaling

Yinong Zong, Bin Zhang, Shenyan Gu, Kwangkook Lee, Jie Zhou, Guorui Yao, Dwight Figueiredo, Kay Perry, Lin Mei, Rongsheng Jin

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

Synapses are the fundamental units of neural circuits that enable complex behaviors. The neuromuscular junction (NMJ), a synapse formed between a motoneuron and a muscle fiber, has contributed greatly to understanding of the general principles of synaptogenesis as well as of neuromuscular disorders. NMJ formation requires neural agrin, a motoneuron-derived protein, which interacts with LRP4 (low-density lipoprotein receptor-related protein 4) to activate the receptor tyrosine kinase MuSK (muscle-specific kinase). However, little is known of how signals are transduced from agrin to MuSK. Here, we present the first crystal structure of an agrin-LRP4 complex, consisting of two agrin-LRP4 heterodimers. Formation of the initial binary complex requires the z8 loop that is specifically present in neuronal, but not muscle, agrin and that promotes the synergistic formation of the tetramer through two additional interfaces. We show that the tetrameric complex is essential for neuronal agrin-induced acetylcholine receptor (AChR) clustering. Collectively, these results provide new insight into the agrin-LRP4- MuSK signaling cascade and NMJ formation and represent a novel mechanism for activation of receptor tyrosine kinases.

Original languageEnglish (US)
Pages (from-to)247-258
Number of pages12
JournalGenes and Development
Volume26
Issue number3
DOIs
StatePublished - Feb 1 2012

Keywords

  • Crystal structure
  • Motoneurons
  • Neuromuscular junction
  • Receptor tyrosine kinase
  • Synapse
  • Synaptogenesis

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Zong, Y., Zhang, B., Gu, S., Lee, K., Zhou, J., Yao, G., Figueiredo, D., Perry, K., Mei, L., & Jin, R. (2012). Structural basis of agrin-LRP4-MuSK signaling. Genes and Development, 26(3), 247-258. https://doi.org/10.1101/gad.180885.111