[Editors] MIT finds most complex protein knot ever seen

[Elizabeth Thomson]

MIT News Office
Massachusetts Institute of Technology
Room 11-400
77 Massachusetts Avenue
Cambridge, MA  02139-4307
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http://web.mit.edu/newsoffice/www

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MIT finds most complex protein knot ever seen
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For Immediate Release
WEDNESDAY, SEP. 20, 2006
Contact: Elizabeth A. Thomson, MIT News Office
Phone: 617-258-5402
Email: thomson at mit.edu

IMAGES AVAILABLE

CAMBRIDGE, Mass.--An MIT team has discovered the most complicated 
knot ever seen in a protein, and they believe it may be linked to the 
protein's function as a rescue agent for proteins marked for 
destruction.

"In proteins, the three-dimensional structure is very important to 
the function, and this is just one example," said Peter Virnau, a 
postdoctoral fellow in physics and an author of a paper on the work 
that appears in the Sept. 15 issue of the Public Library of Science, 
Computational Biology.

Knots are rare in proteins - less than 1 percent of all proteins have 
any knots, and most are fairly simple. The researchers analyzed 
32,853 proteins, using a computational technique never before applied 
to proteins at this scale.

Of those that had knots, all were enzymes. Most had a simple 
three-crossing, or trefoil knot, a few had four crossings, and the 
most complicated, a five-crossing knot, was initially found in only 
one protein - ubiquitin hydrolase.

That complex knot may hold some protective value for ubiquitin 
hydrolase, whose function is to rescue other proteins from being 
destroyed - a dangerous job.

When a protein in a cell needs to be destroyed, it gets labeled with 
another protein called ubiquitin. "It's a death mark for the 
protein," said Leonid Mirny, an author of the paper and an associate 
professor in the MIT-Harvard Division of Health Sciences and 
Technology.

Once the "death mark" is applied, proteins are shuttled to a cell 
structure called a proteasome, which pulls the protein in and chops 
it into pieces. However, if ubiquitin hydrolase intervenes and 
removes the ubiquitin, the protein is saved.

The complicated knot found in ubiquitin hydrolase may prevent it from 
getting sucked into the proteasome as it works, Mirny said. The 
researchers hypothesize that proteins with complex knots can't be 
pulled into the proteasome as easily, and the knots may make it 
harder for the protein to unfold, which is necessary for degradation.

The same knot is found in ubiquitin hydrolase in humans and in yeast, 
supporting the theory that there is a connection between the knot and 
the protein's function. This also seems to suggest that the knot has 
been "highly preserved throughout evolution," Virnau said.

Until now, scientists have not paid much attention to knots in 
proteins, but the MIT researchers hope their work will ignite further 
interest in the subject. "We just hope this will become a part of the 
routine crystallographers and NMR spectroscopists do when they solve 
a structure," Mirny said.

Virnau is working on a computer program and a web server, soon to be 
publicly available, that can analyze the structure of any protein to 
see if it has knots, which he believes could be helpful to 
researchers in structural genomics. (Structural genomics aims to 
determine the structure of all proteins produced by a given organism.)

Since their initial screening, the researchers have discovered 
five-crossing knots in two other proteins - a brain protein whose 
overexpression and mutations are linked with cancer and Parkinson's 
disease, and a protein involved in the HIV replication cycle.

They have also found examples of proteins that are closely related 
and structurally similar except for the presence or absence of a 
knot. Two versions of the enzyme transcarbamylase, from humans and 
certain bacteria, catalyze different reactions, depending on whether 
or not there is a knot. The researchers speculate that somewhere 
along the evolutionary line, the sequence that allowed a protein to 
form the knot was added or deleted.

The third author on the paper is Mehran Kardar, an MIT physics 
professor. The research was funded by the National Science Foundation 
and the German Research Foundation.

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Written by Anne Trafton, MIT News Office