9snu
TKD of human Muscle Specific Kinase (MuSK) S752D mutant
Structural highlights
DiseaseMUSK_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. FunctionMUSK_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] Publication Abstract from PubMedMuscle-Specific Kinase (MuSK) is a receptor tyrosine kinase essential for neuromuscular junction (NMJ) formation and maintenance, yet its regulation remains poorly understood. Crystallographic studies of wild-type MuSK revealed an autoinhibited conformation with tyrosines in the activation loop (A-loop) anchored within the catalytic cleft to stabilize the closed, inactive conformation. We showed previously that additional phosphorylation of an A-loop serine may 'prime' MuSK for activation to sensitize it to ligand(s) in certain settings. Here, we employed crystallography, biochemical assays, and hydrogen-deuterium exchange and mass spectrometry (HDX-MS) to test this hypothesis. We found that introducing a phosphomimetic S752D mutation disrupts autoinhibitory A-loop interactions to increase ATP-binding affinity and catalytic turnover. Using HDX-MS, we further observed that the S752D mutation increases A-loop structural flexibility to relieve autoinhibition. The S752D mutation also stabilizes the juxtamembrane NPXY motif region, a docking site for the adaptor Dok7, possibly priming MuSK for downstream signaling. Together, these findings reveal dynamic transitions that underlie relief of MuSK autoinhibition and provide a mechanistic framework for understanding MuSK activation at the NMJ. An S752D activation loop mutation dynamically primes Muscle-Specific Kinase for activation.,Promer JJ, Murphy JW, Lemmon MA, Tsutsui Y, Herbst R Biochem J. 2026 Jul 8;483(7):1221-1235. doi: 10.1042/BCJ20260159. PMID:42240394[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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