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Structural mechanisms of the agrin–LRP4–MuSK signaling pathway in neuromuscular junction differentiation

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Abstract

The neuromuscular junction (NMJ) is the most extensively studied model of neuronal synaptogenesis. Acetylcholine receptor (AChR) clustering on the postsynaptic membrane is a cardinal event in the differentiation of NMJs. AChR clustering and postsynaptic differentiation is orchestrated by sophisticated interactions among three proteins: the neuron-secreted proteoglycan agrin, the co-receptor LRP4, and the muscle-specific receptor tyrosine kinase MuSK. LRP4 and MuSK act as scaffolds for multiple binding partners, resulting in a complex and dynamic network of interacting proteins that is required for AChR clustering. In this review, we discuss the structural basis for NMJ postsynaptic differentiation mediated by the agrin–LRP4–MuSK signaling pathway.

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Abbreviations

AChR:

Acetylcholine receptor

Fz-CRD:

Frizzled cysteine-rich domain

Ig-like:

Immunoglobulin-like

LG:

Laminin globular

LRP4:

Low-density lipoprotein receptor-related protein 4

MuSK:

Muscle-specific kinase

NMJ:

Neuromuscular junction

NtA:

N-terminal agrin

PH:

Pleckstrin homology

PTB:

Phosphotyrosine binding

RTK:

Receptor tyrosine kinase

Tid1:

Tumorous imaginal disc 1

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Acknowledgments

We apologize to our colleagues whose work could not be individually cited due to space limitations. R.J. acknowledges support from the Alfred P. Sloan Foundation.

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  1. Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Yinong Zong & Rongsheng Jin

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Zong, Y., Jin, R. Structural mechanisms of the agrin–LRP4–MuSK signaling pathway in neuromuscular junction differentiation. Cell. Mol. Life Sci. 70, 3077–3088 (2013). https://doi.org/10.1007/s00018-012-1209-9

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