Abstract
The Z-disk of striated and cardiac muscle sarcomeres is one of the most densely packed cellular structures in eukaryotic cells1. It provides the architectural framework for assembling and anchoring the largest known muscle filament systems by an extensive network of protein-protein interactions, requiring an extraordinary level of mechanical stability. Here we show, using X-ray crystallography, how the amino terminus of the longest filament component, the giant muscle protein titin, is assembled into an antiparallel (2:1) sandwich complex by the Z-disk ligand telethonin. The pseudosymmetric structure of telethonin mediates a unique palindromic arrangement of two titin filaments, a type of molecular assembly previously found only in protein-DNA complexes. We have confirmed its unique architecture in vivo by protein complementation assays, and in vitro by experiments using fluorescence resonance energy transfer. The model proposed may provide a molecular paradigm of how major sarcomeric filaments are crosslinked, anchored and aligned within complex cytoskeletal networks.
| Original language | English |
|---|---|
| Journal | Nature |
| Volume | 439 |
| Issue number | 7073 |
| Pages (from-to) | 229-233 |
| Number of pages | 5 |
| ISSN | 0028-0836 |
| DOIs | |
| Publication status | Published - 12.01.2006 |
Funding
Acknowledgements We thank D. Fürst for the gift of antibodies; R. Kühnemuth for discussions on the FRET experiments; M. Forster for involvement in expression and purification tests; G. Burenkov for assistance during data collection at beamline BW6 at MPG-ASMB/DESY; E. Mandelkow and M. von Bergen for making the fluorimeter at MPG-ASMB/DESY available; and E. Ehler for the preparation of neonatal rat cardiomyocyte cultures. N.P. and S.L. were supported by the EU research and training network CAMKIN to M.W. and M.G., respectively. During involvement at the project, O.M. was supported by an EU Marie-Curie postdoctoral fellowship.
