3V65: Crystal Structure Of Agrin And Lrp4 Complex

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.
PDB ID: 3V65Download
MMDB ID: 99014
PDB Deposition Date: 2011/12/18
Updated in MMDB: 2012/04
Experimental Method:
x-ray diffraction
Resolution: 3.3  Å
Source Organism:
Similar Structures:
Biological Unit for 3V65: tetrameric; determined by author
Molecular Components in 3V65
Label Count Molecule
Proteins (4 molecules)
Agrin(Gene symbol: Agrn)
Molecule annotation
Low-density Lipoprotein Receptor-related Protein 4(Gene symbol: Lrp4)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB