An integrated approach to the muscle Z-disk: from atomic structure to human disease (360G-Wellcome-201543_B_16_Z)

£615,549

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 alpha-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.

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Grant Details

Amount Awarded 615549
Applicant Surname Gehmlich
Award Date 2016-04-05T00:00:00+00:00
Financial Year 2015/16
Grant Programme: Title Collaborative Award in Science
Internal ID 201543/B/16/Z
Lead Applicant Dr Katja Gehmlich
Other Applicant(s) Dr Katja Gehmlich, Prof Hugh Watkins, Prof Kristina Djinovic-Carugo, Prof Perry Elliott, Prof Stefan Raunser
Partnership Value 615549
Planned Dates: End Date 2021-02-28T00:00:00+00:00
Planned Dates: Start Date 2016-09-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East