Protein misfolding down to similarities
13 Jul 2011 by Evoluted New Media
A large number of illnesses can be attributed to the misfolding of proteins – researchers in Cambridge and Zurich have discovered proteins tend to fold incorrectly if the sequence of amino acids in a neighbouring section is very similar.
A large number of illnesses can be attributed to the misfolding of proteins – researchers in Cambridge and Zurich have discovered proteins tend to fold incorrectly if the sequence of amino acids in a neighbouring section is very similar.
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Correctly folded (a) and the misfolded (b) structures for a multidomain protein: the positions in the protein marked labelled 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. |
In order to perform their highly specific function, proteins have to adopt a well-defined, three-dimensional structure – in most cases this is done unaided, but the process can go wrong. Misfolded proteins are no longer able to perform their function, in more serious cases, they can clump together and trigger neurodegenerative disease like Alzheimer’s or Parkinson’s disease.
Using single-molecule fluorescence, researchers were able to study the circumstances under which protein misfolding occurs in the largest protein in the body – titin – which helps the stability and elasticity of the muscle fibres.
It is assumed that individual titin domains unfold while the muscle is heavily exerted to avoid damaging the muscle, but when the muscle relaxes, there is a danger these unfolded sections might fold incorrectly. To observe how the protein folds, 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 millimetre, through the energy transfer between probes,” said Professor Benjamin Schuler from the University of Zurich, who led the study.
This enabled the structures of correctly and misfolded proteins to be distinguished and the proportion of misfolding determined. Schuler believes the reason why neighbouring domains have a limited degree of similarity is to prevent protein misfolding.
“The study of different titin domains in our experiments revealed that the probability of misfolding increases if neighbouring domains are very similar in the sequence of their amino acids,” said Schuler. “This seems to be a key evolutionary strategy to avoid protein misfolding and thus guarantee their maximum functionality.”
