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| Hamburg, 11 January 2006 |
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| The giant protein titin helps build muscles
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| Our muscles are composed of piston-like structures called sarcomeres,
made up of many cells. Sarcomeres are linked by thick bands of proteins
called Z-disks. Connections between specific molecules in these bands
orchestrate how the entire structure is formed. |
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Press
Release 11 January 2006 [PDF]
[Deutsch]
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 analysed 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.
Source Article:
P. Zou, N. Pinotsis, S. Lange, Y.-H. Song, A. Popov, I. Mavridis, O.M. Mayans, M. Gautel & M. Wilmanns. Palindromic
assembly of the giant muscle protein titin in the sarcomeric Z-disk. Nature, 12 January 2006
Press Contacts
Anna-Lynn Wegener
EMBL Press Officer, Heidelberg, Germany
Tel: +49 6221 387 8452
E-mail: wegener@embl.de
Melanie Gardner
King's College London, UK
Tel: +44 207 848 3703
E-mail: melanie.gardner@kcl.ac.uk |
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