( etailed image of the connections betwee...)The giant protein titin helps build muscles

The Gautel lab used advanced microscope techniques to watch the molecules link to each other in live cells. "We knew that telethonin acted as a sort of 'cap' or 'bolt' at the end of the titin molecule," Gautel says. "What we couldn't see is how it connected two separate copies of titin together. That's what this study has shown."

Wilmanns adds: "We discovered that telethonin has a kind of internal symmetry that lets it grasp two titin molecules running off in opposite directions. That's new. We've discovered other single proteins that can link to DNA molecules in 'palindromes', but this is the first time we have seen proteins themselves linked like this."

Other molecules enter the Z-disk from sarcomeres on both sides; it is likely, the scientists think, that some of the connections follow the example of titin and telethonin. The groups will now look for other examples. The terminal assembly complex investigated in this work, though, only covers a tiny part of the giant muscle protein titin, which possesses tens of thousands of amino acids in some isoforms. "There are probably hundreds or even thousands of more interactions down the road. We have found one of the first and eagerly anticipate discovering many others, probably coming with lots of surprises," Wilmanns concludes. "We have just started to get insight into one of the most complex systems in the human body."

"This work is a nice example of how modern biology combines approaches from cell biophysics and structural biology, and it gives us a way to discover why some mutations in titin are linked to diseases," says Gautel.