1. EMBL-Hamburg c/o DESY, Notkeststrasse 85, D-22603 Hamburg, Germany
2. Institute of Physical Chemistry, National Center for Scientific Research 'Demokritos', Aghia Paraskevi 15310, Athens, Greece
3. The Randall Division of Cell and Molecular Biophysics and Cardiovascular Division, King's College London, Guy's Campus, London SE1 1UL, UK
4. Institute of Cell Biology, ETH Zurich Hoenggerberg, CH-8093 Zurich, Switzerland
5. Biozentrum, University of Basel, Division of Structural Biology, Klingelbergstrasse 70, CH-4056 Basel, Switzerland
6. *These authors contributed equally to this work

Correspondence to: Matthias Wilmanns¹ Correspondence and requests for materials should be addressed to M.W. (Email: wilmanns@embl-hamburg.de). Coordinates and structure factors have been deposited in the Protein Data Bank under accession number 1YA5.

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.

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