The three-dimensional structure of a type I module from titin: a prototype of intracellular fibronectin type III domains.
BACKGROUND
Titin is a huge protein ( approximately 3 MDa) that is present in the contractile unit (sarcomere) of striated muscle and has a key role in muscle assembly and elasticity. Titin is mainly composed of two types of module (type I and II). Type I modules are found exclusively in the region of titin localised in the A band, where they are arranged in a super-repeat pattern that correlates with the ultrastructure of the thick filament. No structure of a titin type I module has been reported so far.


RESULTS
We have determined the structure of a representative type I module, A71, using nuclear magnetic resonance (NMR) spectroscopy. The structure has the predicted fibronectin type III fold. Titin-specific conserved residues are either located at the putative module-module interfaces or along one side of the protein surface. Several proline residues that contribute to two stretches in a polyproline II helix conformation are solvent-exposed and line up as a continuous ribbon extending over more than two-thirds of the module surface. Homology models of the type I module N-terminal to A71 (A70) and the double module A70-A71 were used to discuss possible intermodule interactions and their role in module-module orientation.


CONCLUSIONS
As residues at the module-module interfaces are highly conserved, we speculate that similar interactions govern all of the interfaces between type I modules in titin. This conservation would lead to a regular multiple array of similar surface structures. Such an arrangement would allow arrays of contiguous type I modules to expose multiple proline stretches in a highly regular way and these may act as binding sites for other thick filament proteins.
Goll
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CM
EMBL Meyerhofstrasse 1, 69117, Heidelberg, Germany Institut de Biologie Structurale J-P Ebel 41 Avenue des Martyrs, 38027 Grenoble, France.
Pastore
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A
Nilges
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D000595:Amino Acid Sequence; D000818:Animals; D003196:Computer Graphics; D064211:Connectin; D005353:Fibronectins / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D018656:Muscle Fibers, Fast-Twitch / Q000502:physiology; D009124:Muscle Proteins / Q000737:chemistry* / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology; D019906:Nuclear Magnetic Resonance, Biomolecular; D011494:Protein Kinases / Q000737:chemistry* / Q000502:physiology; D017433:Protein Structure, Secondary; D012518:Sarcomeres / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D064211:Connectin; D005353:Fibronectins; D008565:Membrane Proteins; D009124:Muscle Proteins; D011494:Protein Kinases