Structural basis of agrin–LRP4–MuSK signaling

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.

Wnts contribute to neuromuscular junction formation through distinct signaling pathways

“…Activation of this complex is required for: (1) the early, nerveindependent muscle prepatterning, as characterized by acetylcholine receptor (AChR) aggregation in the prospective synaptic region of the muscle surface that helps to guide growing motor axons towards their final target; and (2) the late, nerve-dependent differentiation and maturation of the synapse (Tintignac et al, 2015). This later step is orchestrated by the release of a nerve secreted isoform of agrin, which binds to muscle Lrp4 leading to activation of MuSK and AChR clustering in the postsynaptic membrane Zhang et al, 2008Zhang et al, , 2011Zong et al, 2012).…”

β-Catenin gain of function in muscles impairs neuromuscular junction formation

“…NMJ formation is regulated by interactions between motoneurons and muscles Wu et al, 2010). Motoneurons release agrin, which binds directly to LRP4 and thus activates MuSK, both of which are required for NMJ formation (McMahan, 1990;DeChiara et al, 1996;Gautam et al, 1996;Glass et al, 1996;Weatherbee et al, 2006;Kim, N. et al, 2008;Zhang et al, 2008;Zong et al, 2012). By contrast, activation of muscles by acetylcholine (ACh) from motoneurons suppresses the expression of acetylcholine receptors (AChRs) and dissembles AChR clusters (Schaeffer et al, 2001;Misgeld et al, 2002;Brandon et al, 2003;Chen et al, 2007).…”

Schwann Cells in Neuromuscular Junction Formation and Maintenance

“…The aneural clusters are thought to contribute to forming larger, synaptic AChR aggregates, in response to innervation, and outline a region that attract nerve terminals (Flanagan-Steet et al, 2005;Jing et al, 2009). Nerve induction of AChR clustering requires agrin, an extracellular proteoglycan, which acts by stimulating the Lrp4-MuSK receptor complex (Godfrey et al, 1984;Nitkin et al, 1987;McMahan, 1990;Ruegg et al, 1992;Kim et al, 2008;Zhang et al, 2008;Zong et al, 2012). Primitive, extrasyn-aptic AChR clusters are dispersed by muscle activity, caused by AChR activation by ACh (Avila et al, 1989;Misgeld et al, 2002;Brandon et al, 2003).…”