Muscle-Specific Kinase Transmembrane Helices: Stability and Interactions in Detergent Micelles vs. Lipid Bilayers

Signal transduction is essential for many biological processes, such as mitosis, cell regeneration, and muscle contraction. Muscle-Specific Kinase (MuSK) is in a complex with low-density lipoprotein receptor-related protein 4 (LRP4), and upon binding of the substrate Agrin to LRP4, conformational changes of these proteins initiate a signalling cascade, stimulating aggregation of acetylcholine receptors (AChRs), which results the downstream organization of neuromuscular synapses. Mutations and/or autoantibodies against MuSK affects its ability to aggregate acetylcholine receptors, resulting in the disease myasthenia gravis, which is characterised by impaired muscle contractions. Approximately 70% of the structure of the full-length MuSK protein has been determined (consisting of the most of the extracellular domain and the intracellular kinase domain). However, crucially the transmembrane domain has not been characterised, and the structure of the transmembrane dimer that MuSK forms has not been determined. Here we apply a multi-scale MD simulation method to examine at the behaviour of MuSK TM helices in a lipid bilayer vs. a detergent micelle environment. Coarse-grained (CG) simulations, which make an extended timescale readily accessible, are used to examine initial TM helix dimerisation events. Subsequent atomistic simulations serve to refine the model of the interactions observed in CG simulations. These computational studies highlight the effect of lipids vs. detergents on the interactions of the transmembrane helices within the dimer.