FOR 1352: Structure, Function and Regulation of the Myofibrillar Z-disc Interactome
Final Report Abstract
Traditionally the myofibrillar Z-disc was envisioned merely as a stable structure linking thin filaments from neighboring sarcomeres and passively transmitting force during contraction. This classic view of the Z-disc has strongly changed upon the discovery of a plethora of new Z-disc proteins and their pleiotropic functions in development, protein homeostasis and signal transduction. The importance of the Z-disc is further emphasized by the finding that mutations in genes encoding several Z-disc proteins cause neuromuscular diseases and/or cardiomyopathies. The central aim of FOR1352 was to define the precise molecular layout of the Z-disc, its dynamics and its role in signal transduction. In line with the formulated goals of the two granting periods, the groups participating in FOR1352 have provided a plethora of substantial contributions addressing 1) the functional characterization of Z-disc proteins and their regulation in cell and animal models, 2) a compilation of the Z-disc proteome and of its functional subcomplexes, 3) structural information of the Z-disc at the molecular and supramolecular levels, 4) the analysis of the biophysical and biomechanical properties at the levels of single proteins and selected complexes, as well as 5) the regulation of the homeostasis of Z-discassociated proteins. An outstanding achievement of FOR1352 was the compilation of the Z-disc proteome to the greatest possible extent and to define functional subcomplexes. Our work has also illustrated an unanticipated dynamic behaviour of Z-disc proteins. Quantitative phosphoproteome analyses have for the first time allowed to define signalling pathways, which regulate the precise composition of these protein complexes by phosphorylations, and which substantially modulate protein dynamics. The outcome of our successful analysis of a large number of protein complexes by applying a panel structural biology and biophysics techniques is an increasingly clear image of the structural layout of Z-disc proteins and their interactions. Our investigations on the homeostasis of filamin C have enabled us to unravel "chaperone-assisted selective autophagy" (CASA) as a novel, tension-dependent mechanism regulating protein homeostasis. It turned out that CASA does not only play an important role in the pathogenesis of muscular diseases, but is of general importance for the essential continuous repair of lesions of the contractile apparatus. A further, successfully implemented focus of FOR1352 was the generation and systematic characterisation of numerous animal and cell models specifically dedicated to the functional analysis of Z-disc proteins. Of particular interest in this context are mouse models allowing to analyse the in vivo function of titin, as well as cell models enabling to determine protein dynamics and to localise specific protein-protein interactions. Taken together, FOR1352 - with its high level of international visability - has provided invaluable contributions to our current knowledge of the biochemical properties of Z-disc proteins and their biological functions. Thus, our work has led to a fundamentally improved understanding of the myofibrilar Z-disc, which has allowed us to gain far broader insight into the molecular basis of heart and skeletal muscle function in both health and disease.
