An integrated approach to the muscle Z-disk: from atomic structure to human disease (360G-Wellcome-201543_C_16_Z)

Contraction of heart and skeletal muscles relies on the highly regular assembly of two main contractile protein filaments, actin and myosin, into sarcomeres. Actin and myosin are cross-linked in transverse planes in parallel arrays of interdigitating filaments, enabling their sliding motion to generate force. Antiparallel actin filaments are cross-linked at the Z-disk, requiring the coordinated action of the cross-linker α-actinin and the sarcomeric blueprint titin. Z-disks are stable yet flexible tensegrity networks acting possibly not only as mechanical integrators, but also as mechanosignalling platforms via protein kinases, phosphatases and adaptor proteins, sensing and relaying information on biomechanical stress. The Z-disk is extremely hard to analyse by conventional top-down ultrastructural methods, and we will hence pursue a bottom-up molecular approach. Mutations in Z-disk protein genes and those controlling its turnover are emerging as major causes of dilated and hypertrophic cardiomyopathy (DCM, HCM), left-ventricular non-compaction (LVNC), myofibrillar myopathy (MFM) and others. Our work will unravel how Z-disk mechanical, architectural and signalling functions operate from the atomic to the cellular and physiological level and how it is disrupted by cardiomyopathy mutations. This insight will allow better understanding of novel disease-causing mutations in Z-disk genes and reiteratively drive the fidelity of variant interpretation.