Huge Protein Titin Helps Build Muscles

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Huge Protein Titin Helps Build Muscles

http://www.medicalnewstoday.com/medicalnews.php?newsid=36071

Imagine grabbing two snakes by the tail so that they can't wriggle

off in opposite directions. Scientists at the Hamburg Outstation of

the European Molecular Biology Laboratory (EMBL) and collaborators

from King's College in London have now discovered that something

similar happens to a protein that is crucial in the formation of

muscle tissue. Their work appears in the current issue of the journal

Nature.

Under the microscope, muscle looks like millions of tiny pistons,

stacked end-to-end into long rows. These structures, called

sarcomeres, permit the contraction and relaxation of muscle that

allow our bodies to move. Sarcomeres are connected at the ends by Z-

disks, thick bands of densely-packed molecules. " Sarcomeres are very

complex structures, and for many years we've been investigating the

steps by which they are formed, " says Matthias Wilmanns, Head of the

EMBL Hamburg Outstation. " That probably starts when proteins link up

to each other in very big assemblies. The meeting point is the Z-

disk, but unraveling the connections has been difficult. "

Wilmanns' lab and the team of Mathias Gautel, an EMBL alumnus and now

at King's College, have thought that a molecule called titin, the

largest protein made by human cells, is involved. Titin is anchored

in the Z-disk and is so long that it spans half the length of a

sarcomere. Its size and position - putting it into contact with all

the major components of sarcomeres - suggests that it might help in

their assembly.

The latest study, which arises from more than a decade of

collaborative research by the Wilmanns and Gautel teams, gives a

solution to how this might happen. Peijian Zou and Nikos Pinotsis

from the Wilmanns lab obtained crystals of parts of the titin

molecule bound to another protein, called telethonin. They analyzed

the crystals on high-energy X-ray beamlines at EMBL's Hamburg

station, on the site of the German Electron Synchrotron Radiation

Facility (DESY). From the extremely detailed image of the connections

between the proteins they discovered that telethonin links the tails

in a unique way that may give some clues to sarcomere assembly.

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.