9lgg

Structural highlights

Disease

MUSK_HUMAN Postsynaptic congenital myasthenic syndromes;Fetal akinesia deformation sequence. The disease is caused by variants affecting the gene represented in this entry. MUSK mutations lead to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. The disease is caused by variants affecting the gene represented in this entry.

Function

MUSK_HUMAN Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle (PubMed:25537362). Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. May regulate AChR phosphorylation and clustering through activation of ABL1 and Src family kinases which in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex with MUSK are also important for MUSK-dependent regulation of AChR clustering. May positively regulate Rho family GTPases through FNTA. Mediates the phosphorylation of FNTA which promotes prenylation, recruitment to membranes and activation of RAC1 a regulator of the actin cytoskeleton and of gene expression. Other effectors of the MUSK signaling include DNAJA3 which functions downstream of MUSK. May also play a role within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation (By similarity).^[1]

References

1. ↑ Tan-Sindhunata MB, Mathijssen IB, Smit M, Baas F, de Vries JI, van der Voorn JP, Kluijt I, Hagen MA, Blom EW, Sistermans E, Meijers-Heijboer H, Waisfisz Q, Weiss MM, Groffen AJ. Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence. Eur J Hum Genet. 2015 Sep;23(9):1151-7. PMID:25537362 doi:10.1038/ejhg.2014.273