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Titin is the largest polypeptide yet discovered (~3.5 MDa). Single moleules span from the Z- to M-line (yellow in the diagram). These have two main functions: In the thick (myosin) filament part of the myofibril we have proposed the titin molecule regulates exact myosin assembly by acting as a giant template or "protein-ruler". We are exploring this hypothesis by binding assays with myosin using the whole proteins and fragments prepared by proteolysis and cDNA expression.
The remainder of the titin molecule forms an elastic connection between the end of the thick filaments and the Z-line. These connections give muscle its passive tension and they also keep thick filaments centered between Z-discs. (Without this there would be force imbalances in the opposite halves of thick filaments during active contraction).
Professor John Trinick is interested in the molecular mechanism of titin elasticity, which we are studying at the single molecule level by atomic force microscopy and electron microscopy. We proposed that the titin molecule extends by unfolding its polypeptide and we recently demonstrated that this can occur in both the beta-structure domains (from which the molecule is mainly composed) and in a small part of unknown structure called the PEVK region. His 1997 paper in Nature was the first demonstration of the mechanical unfolding of globular protein domains. This work also offers a new approach to study protein folding, which is a major problem in structural biology.
Dr Michelle Peckham is interested in the function of titin in organising muscle sarcomere formation in skeletal and cardiac muscle. Her papers in Journal of Cell Science in 2003 and 2006, showed a critical role for the titin kinase and M-band region of titin in this process.