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Reverse engineering of the giant muscle protein titin


Through the study of single molecules it has become possible to explain the function of many of the complex molecular assemblies found in cells1,2,3,4,5. The protein titin provides muscle with its passive elasticity. Each titin molecule extends over half a sarcomere, and its extensibility has been studied both in situ6,7,8,9,10 and at the level of single molecules11,12,13,14. These studies suggested that titin is not a simple entropic spring but has a complex structure-dependent elasticity. Here we use protein engineering and single-molecule atomic force microscopy15 to examine the mechanical components that form the elastic region of human cardiac titin16,17. We show that when these mechanical elements are combined, they explain the macroscopic behaviour of titin in intact muscle6. Our studies show the functional reconstitution of a protein from the sum of its parts.

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Figure 1: The proximal and distal tandem Ig regions of cardiac titin have different mechanical properties.
Figure 2: Single-molecule AFM measurements of the mechanical properties of the N2B and PEVK regions of titin.
Figure 3: Single-molecule data explain the extensibility of the individual titin segments measured in situ.
Figure 4: Single-molecule data predict the force–extension curve of cardiac muscle.


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We thank H. Erickson for the electron microscope pictures of I27 polyproteins. W.A.L. thanks the German Research Foundation for a Heisenberg fellowship. This work was supported by the National Institutes of Health (J.M.F.)

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Correspondence to Julio M. Fernandez.

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Li, H., Linke, W., Oberhauser, A. et al. Reverse engineering of the giant muscle protein titin. Nature 418, 998–1002 (2002).

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