What mutations tell us about protein folding

Posted by: joann on Oct 18, 2005 - 01:37 AM
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[excerpt]
Scientists continue to be puzzled by how proteins fold into their three-dimensional structures. Small single-domain proteins may hold the key to solving this puzzle. These proteins often fold into their three-dimensional structures by crossing only a single barrier. The barrier consists of an ensemble of extremely short-lived transition state structures which cannot be observed directly. However, mutations that slightly shift the folding barrier may provide indirect access to transition states. Researchers from the Max Planck Institute of Colloids and Interfaces and the University of California, San Francisco have suggested a novel method to construct transition state structures from mutational data (PNAS, July, 2005).

Proteins are chain molecules assembled from amino acids. The precise sequence of the twenty different types of amino acids in a protein chain is what determines which structure a protein folds into. The three-dimensional structures in turn specify the functions of proteins, which range from the transport of oxygen in our blood, to the conversion of energy in our muscles, and the strengthening of our hair. During evolution, the protein sequences encoded in our DNA have been optimised for these functions.

The reliable folding of proteins is a prerequisite for them to function robustly. Mis-folding can lead to protein aggregates that cause severe diseases, such as Alzheimer's, Parkinson's, or the variant Creutzfeldt-Jakob disease. To understand protein folding, research has long focused on metastable folding intermediates, which were thought to guide the unfolded protein chain into its folded structure. It came as a surprise about a decade ago that certain small proteins fold without any detectable intermediates. This astonishingly direct folding from the unfolded state into the folded state has been termed 'two-state folding'€TM. In the past few years, scientists have shown that the majority of small single-domain proteins are 'two-state folders'€TM, which are now a new paradigm in protein folding.

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