Similarities cause protein misfolding

May 31, 2011
This is an illustration of the correctly folded (a) and the misfolded (b) structures for a multidomain protein studied using single-molecule spectroscopy. The positions in the protein labeled with dye probes are shown as orange balls. The structure in (b) arises from the combination of spectroscopic distance measurements in the molecule and simulations. Credit: UZH

A large number of illnesses stem from misfolded proteins, molecules composed of amino acids. Researchers at the University of Zurich have now studied protein misfolding using a special spectroscopic technique. Misfolding, as they report in Nature, is more frequent if the sequence of the amino acids in the neighboring protein domains is very similar.

A large number of illnesses stem from misfolded proteins, molecules composed of amino acids. Researchers at the University of Zurich have now studied misfolding using a special spectroscopic technique. Misfolding, as they report in Nature, is more frequent if the sequence of the amino acids in the neighboring protein domains is very similar.

Proteins are the main molecular machines in our bodies. They perform a wide range of functions, from digesting and processing nutrients, converting energy and aiding to transmitting signals in cells and the whole body. In order to perform these highly specific functions, proteins have to adopt a well-defined, three-dimensional structure. Remarkably, in most cases they find this structure unaided once they have been formed out of their individual building blocks, amino acids, as a long chain molecule in the cell.

However, the process of can also go wrong, which means the proteins affected are no longer able to perform their function. In some cases, this can even have much more serious consequences if these misfolded proteins clump and trigger such as Alzheimer's or .

In the course of evolution, a crucial factor in the development of proteins has thus been to avoid such "misfolding processes". However, this is no easy task since the same that stabilize the correct structure of the individual proteins can also bring about interactions between , causing them to misfold.

Using a special spectroscopic method called single-molecule fluorescence, researchers from the Universities of Zurich and Cambridge have now studied the circumstances under which misfolding occurs. The team headed by Prof. Benjamin Schuler from the University of Zurich studied sections, or "domains", of the largest protein in our bodies, titin, which helps the stability and elasticity of the muscle fibers. It is assumed that individual titin domains can unfold while the muscle is heavily exerted to avoid damaging the muscle tissue. When the muscle relaxes again, however, there is a danger that these unfolded domains might fold incorrectly. There is also a similar risk for other multidomain proteins.

For their study, the researchers attached small dye molecules as probes in the protein. "Using our laser-spectroscopic method we were able to determine distances on a molecular scale, i.e. down to a few millionths of a millimeter, through the energy transfer between the probes," explains Prof. Schuler. This enabled the structures of correctly and misfolded proteins to be distinguished and thus the proportion of misfolding determined.

"The study of different titin domains in our experiments revealed that the probability of misfolding increases if neighboring domains are very similar in the sequence of their ," says Prof. Schuler. This is apparently the reason why neighboring domains in proteins have a limited degree of similarity. "This seems to be a key evolutionary strategy to avoid and thus guarantee their maximum functionality," says Schuler.

Explore further: Tarantula toxin is used to report on electrical activity in live cells

Provided by University of Zurich

1 /5 (1 vote)
add to favorites email to friend print save as pdf

Related Stories

Unfolding 'nature's origami'

Mar 02, 2009

Sometimes known as "nature's origami", the way that proteins fold is vital to ensuring they function correctly. But researchers at the University of Leeds have discovered this is a 'hit and miss' process, with proteins potentially ...

Gently unfolding proteins to watch them refold

Jun 07, 2010

(PhysOrg.com) -- How does a protein chain fold into the same 3-D shape each time and not something disfunctional or dangerous? A new study shows that the first fold is critical. The finding ...

Research breakthrough for the protein factories of tomorrow

Sep 22, 2006

Using a kind of molecular ‘hip joint operation,’ researchers at Uppsala University have succeeded in replacing a natural amino acid in a protein with an artificial one. This step forward opens the possibility of creating ...

Recommended for you

Scientists see how plants optimize their repair

8 hours ago

Researchers led by a Washington State University biologist have found the optimal mechanism by which plants heal the botanical equivalent of a bad sunburn. Their work, published in the Proceedings of the Na ...

Structure of an iron-transport protein revealed

14 hours ago

For the first time, the three dimensional structure of the protein that is essential for iron import into cells, has been elucidated. Biochemists of the University of Zurich have paved the way towards a better ...

Over-organizing repair cells set the stage for fibrosis

14 hours ago

The excessive activity of repair cells in the early stages of tissue recovery sets the stage for fibrosis by priming the activation of an important growth factor, according to a study in The Journal of Ce ...

User comments : 2

Adjust slider to filter visible comments by rank

Display comments: newest first

LariAnn
1 / 5 (1) May 31, 2011
"Evolutionary strategy"? How can something that is supposed to have been the result of random molecular interaction possess a "strategy"?
mattbroderick
not rated yet May 31, 2011
"Evolutionary strategy"? How can something that is supposed to have been the result of random molecular interaction possess a "strategy"?


This is a common phrasing both inside and outside of the science community, even though technically incorrect. It is anthropomorphizing -- using the perspective of genetic material in the 1st person. High rates of improper folds have proven deleterious, thus proteins with similar domains are selected against. The genetic material can be said to have employed this specific strategy (ex post facto, of course).