Structural basis of agrin–LRP4–MuSK signaling
- 1 February 2012
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 26 (3), 247-258
- https://doi.org/10.1101/gad.180885.111
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.Keywords
This publication has 60 references indexed in Scilit:
- Structural and Functional Studies of LRP6 Ectodomain Reveal a Platform for Wnt SignalingDevelopmental Cell, 2011
- Structural Basis of Wnt Signaling Inhibition by Dickkopf Binding to LRP5/6Developmental Cell, 2011
- Cell Signaling by Receptor Tyrosine KinasesCell, 2010
- HSP90β Regulates Rapsyn Turnover and Subsequent AChR Cluster Formation and MaintenanceNeuron, 2008
- Lrp4 Is a Receptor for Agrin and Forms a Complex with MuSKCell, 2008
- LRP4 Serves as a Coreceptor of AgrinNeuron, 2008
- Defective Neuromuscular Synaptogenesis in Agrin-Deficient Mutant MiceCell, 1996
- The Receptor Tyrosine Kinase MuSK Is Required for Neuromuscular Junction Formation In VivoCell, 1996
- Synaptic structure and development: The neuromuscular junctionCell, 1993
- Agrin isoforms and their role in synaptogenesisCurrent Opinion in Cell Biology, 1992