At their birth, amino acid chains face a problem: they must fold up correctly into a fully functional protein that is productive for the cell. The folding can occur in countless ways but only one way is correct. In brief, the protein must solve a sort of Rubik's cube at the nanoscale. Up until now it has been assumed that random movements of the chain eventually resulted in the correct shape. Research in the laboratory of prof.dr.ir. Sander Tans has shown that this is not the full story. The molecular puzzle is actively solved by 'players': other proteins that physically grab hold of the folding chain and push it into the correct shape.
The players of the molecular Rubik's cube are called chaperones. For a long time it has been known that chaperone proteins are important for the formation of new proteins. However, up until now it was thought that they only performed two tasks: holding the sticky amino acid chains apart before the start of the folding process to prevent large lumps of protein from forming and helping to unfold wrongly folded proteins so that the protein can make a new attempt.
The new research made it clear that a chaperone, called 'Trigger Factor', grabs proteins during the folding and by doing this helps to solve the folding puzzle. How that happens is surprisingly simple and elegant. Several chaperones bind to a single amino acid chain and divide the problem into simpler, smaller subproblems. This allows an amino acid chain to fold independently at several locations and therefore form a complex protein without error. This general principle also immediately explains how one type of chaperone can bind to so many different types of protein and help these to fold.
The researchers made this breakthrough possible by measuring a single folding protein. They attached small plastic beads to the folding protein, which were in turn picked up by a laser beam. As folding makes the amino acid chains shorter, the beads shifted and the laser registered that. This allowed the researchers to follow the folding process by measuring the length of the chains.
The researchers saw that the protein assumed different lengths step-by-step. This indicated that at some moment the protein was partially folded, an effect that can be attributed to the chaperones that stabilized the folded part of the protein. Without the help of the chaperones the protein would change from unfolded to completely folded in a single step.
A better understanding of protein folding is very important for medicine. Proteins lie at the basis of all biological functionality. If something goes wrong with the folding then the proteins are not productive and then they also remain sticky. This stickiness seems to underlie many diseases, including Alzheimer's disease, and ageing. The study also reveals that current computer simulations of the folding process miss a vital component: the players that make the folding possible.
Reshaping of a protein conformational search by the chaperone Trigger Factor , Alireza Mashaghi1, Günter Kramer2, Philipp Bechtluft1, Beate Zachmann-Brand2, Arnold J. M. Driessen3, Bernd Bukau2 & Sander J. Tans1
1 AMOLF Institute, the Netherlands
2 Centre for Molecular Biology, Heidelberg University, Germany
3 Department of Molecular Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute and the Zernike Institute for Advanced Materials, the Netherlands
See also: press release RUG