RGD Reference Report - Structural basis of agrin-LRP4-MuSK signaling. - Rat Genome Database

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Structural basis of agrin-LRP4-MuSK signaling.

Authors: Zong, Y  Zhang, B  Gu, S  Lee, K  Zhou, J  Yao, G  Figueiredo, D  Perry, K  Mei, L  Jin, R 
Citation: Zong Y, etal., Genes Dev. 2012 Feb 1;26(3):247-58. doi: 10.1101/gad.180885.111.
RGD ID: 8553690
Pubmed: PMID:22302937   (View Abstract at PubMed)
PMCID: PMC3278892   (View Article at PubMed Central)
DOI: DOI:10.1101/gad.180885.111   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of protein phosphorylation involved_inIMP 8553690PMID:22302937UniProt 
skeletal muscle acetylcholine-gated channel clustering involved_inIMP 8553690PMID:22302937UniProt 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding enablesIPIUniProtKB:Q9QYP18553690PMID:22302937UniProt 
protein binding enablesIPIUniProtKB:P253048553690PMID:22302937UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Agrn  (agrin)
Lrp4  (LDL receptor related protein 4)


Additional Information