the largest gene product of the human genome, comprises up to 38,000
in its largest isoform and is organised into about 300 protein domains,
which the majority are folded as immunoglobulin (Ig)-like domains or
fibronectin type-III (FN-III)-like domains (Figure 1). It is known as the third
filament of the muscle sarcomere and is involved in multiple functions,
acting as a "molecular ruler" to align major components of the
sarcomere, as well as muscle development, passive elasticity, and
than a decade's efforts have led to the identification of a
protocol that has allowed us to crystallise the N-terminal assembly
titin in the absence and presence of the Z-disk protein telethonin (Zou et al.
2003; Marino et al.
2006; Zou et
al. 2006). To our surprise, the structure
revealed a (2:1)
sandwich complex, characterised by two titin molecules assembled by
acting as a mediator, with pseudo-palindromic symmetry (Figure 2). Folding of the
N-terminal part of telethonin is induced by the presence of titin,
made structural analysis of separate telethonin impossible, to date. In
to independently validate our structural findings, we developed a
site-specifically label the titin/telethonin complex to allow a
The following further structures were determined by our group during the reporting period: the Ig-tandem arrangement A168-A169 of titin, near the titin kinase domain (Mueller et al., submitted); the M1 Ig-like domain of titin, C-terminal to the titin kinase domain (Mueller et al., unpublished); the PB1 domain of the titin kinase downstream signalling molecule NBR1 (Lange et al. 2005; Muller et al. 2006); the PB1/PB1 domain complex of the downstream signalling components NBR1 and P62 (Mueller et al., unpublished), and the I27 Ig-like domain from the I-band of titin (Vega et al., unpublished).
Figure 3: Model outlining the architecture of the sarcomeric Z-disk. Titin filaments are assembled by a dual Z-disk bridging system, by a-actinin rods on a variable number of titin Z-repeats [three bridges are shown], and by telethonin via the N-terminal IG domains Z1 and Z2.
Prof. Kristina Djinovic-Carugo (University of Vienna, Austria)
Prof. Dieter Fürst (University of Bonn, Germany)
Prof. Mathias Gautel (King's College, London, UK).
Relevant Publications from our Laboratory
Marino, M., Zou, P., Svergun, D., Garcia, P., Edlich, C., Simon, B., Wilmanns, M., Muhle-Goll, C. & Mayans, O. (2006) Structure 14, 1437-1447. The Ig-doublet Z1Z2 Ð a model system for the hybrid analysis of conformational dynamics in Ig tandems from titin.
Pinotsis, N., Petoukhov, M., Lange, S., Svergun, D., Zou, P., Gautel, M., Wilmanns, M. (2006). J. Struct. Biol. 155, 239-250. Evidence for a dimeric assembly of two titin/telethonin complexes induced by the telethonin C-terminus.
Lee, E.H., Gao, M., Pinotsis, N., Wilmanns, M. & Schulten, K. (2006). Structure 14, 497-509. The Mechanical Stability of the Titin Z1Z2/Telethonin Complex revealed by Steered Molecular Dynamics Simulations.
Zou P, Pinotsis, N., Lange, S., Song, Y.-H., Popov, A., Mavridis, I., Mayans, O.M., Gautel, M. & Wilmanns, M. (2006). Nature 439, 229-33. Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk.
Muller, S., Kursula, I., Zou, P. & Wilmanns, M. (2006). FEBS Lett. 580, 341-444. Crystal structure of the PB1 domain of NBR1.
Zou, P., Geerlof, A., Gautel, M., Wilmanns, M., Koch, M. & Svergun, D. (2003). J. Biol. Chem. 278, 2636-44. Stoichiometry and modelling of the titin-telethonin complex suggests a cross-linking function of telethonin.
Gao, M., Wilmanns, M. & Schulten, K. (2002). Biophys. J. 83, 3435-3445. Steered Molecular Dynamics Studies of Titin I1 Domains.
Paavilainen, V.O., Merckel, M., Palmgren, S., Ojala, P.J., Pohl, E., Wilmanns, M. & Lappalainen, P. (2002). J. Biol. Chem. 277, 43089-43095. Structural conservation between the actin monomer-binding sites of twinfilin and ADF/cofilin.
Mayans, O.M., Wuerges, J., Gautel, M. & Wilmanns, M. (2001). Structure 9, 331-340. Structural evidence for a possible role of reversible disulfide bridge formation in elasticity of the muscle protein titin.
Wilmanns, M., Gautel, M. & Mayans, O.M. (2000). Cell. Mol. Biol. 46, 883-894. Activation of calcium / calmodulin regulated kinases.
Mayans, O.M. & Wilmanns, M. (1999). J. Synchr. Rad. 6, 1016-1020. X-ray analysis of protein crystals with thin plate morphology.
O.M., Van der Ven, P. D.M., Wilm, M., Mues, A., Young, P., Fürst,
M. & Gautel, M. (1998). Nature 395, 863-869. The structural
basis of the activation mechanism of the
serine kinase domain of the giant muscle protein titin during
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