Abstracts
Karl Lohmann Prize
Structural Investigation of the Relaxed Cardiac Sarcomere by Electron Cryo-Tomography
Davide Tamborrini
Basel Univeristy, Biocenter, <a>davide.tamborriniunibasch</a>
The sarcomere is the basic unit of striated muscles and consists of interdigitating thick and thin filaments. The two types of filaments slide on each other, resulting in the shortening of sarcomere itself, thereby generating work. The thin filament comprises filamentous actin (F-actin), troponin (Tn), and tropomyosin (Tm). The thick filament is the force-bearing part of the sarcomere, and it comprises myosin, titin, and myosin-binding protein C (MyBP-C). The vast majority of the mutations responsible for familial hypertrophic cardiomyopathy and other heart and muscle diseases are borne by components of the thick filaments. However, despite its central importance, it remained unclear how thick filaments are structurally organized and how its components interact with each other and with thin filaments to enable highly regulated muscle contraction in the cardiac tissue.
During my PhD, I aimed to elucidate the molecular organization of the thick and thin filaments in the relaxed state. I resorted to cryo-focused ion beam milling (cryo-FIB milling) and cryo-electron tomography (cryo-ET) to investigate the molecular architecture of the native mammalian cardiac sarcomeres.
The reconstruction of the thick filament reveals the three-dimensional organization of myosin, titin and myosin-binding protein C (MyBP-C), clarifying the structural basis of muscle contraction at sub-nanometer resolution. These results provide a molecular blueprint of the cardiac sarcomere and pave the way to forthcoming research aiming to explore muscle disorders involving sarcomeric structural components.