TY - JOUR
T1 - Structural basis of agrin-LRP4-MuSK signaling
AU - Zong, Yinong
AU - Zhang, Bin
AU - Gu, Shenyan
AU - Lee, Kwangkook
AU - Zhou, Jie
AU - Yao, Guorui
AU - Figueiredo, Dwight
AU - Perry, Kay
AU - Mei, Lin
AU - Jin, Rongsheng
PY - 2012/2/1
Y1 - 2012/2/1
N2 - 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.
AB - 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.
KW - Crystal structure
KW - Motoneurons
KW - Neuromuscular junction
KW - Receptor tyrosine kinase
KW - Synapse
KW - Synaptogenesis
UR - http://www.scopus.com/inward/record.url?scp=84863011431&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863011431&partnerID=8YFLogxK
U2 - 10.1101/gad.180885.111
DO - 10.1101/gad.180885.111
M3 - Article
C2 - 22302937
AN - SCOPUS:84863011431
SN - 0890-9369
VL - 26
SP - 247
EP - 258
JO - Genes and Development
JF - Genes and Development
IS - 3
ER -