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What Mutations Tell Us About Protein Folding

October 17, 2005
Max Planck scientists find a novel way to construct transition states for protein folding reactions.

The structure of the protein CI2 consists of an α-helix packed against a β-sheet. CI2 is a ‘two-state protein’ that folds, from the unfolded state into the folded state, by crossing just a single transition state barrier.
Credit: Image : MPI for Colloids and Interfaces

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Proteins are chainmolecules assembled from amino acids. The precise sequence of thetwenty different types of amino acids in a protein chain is whatdetermines which structure a protein folds into. The three-dimensionalstructures in turn specify the functions of proteins, which range fromthe transport of oxygen in our blood, to the conversion of energy inour muscles, and the strengthening of our hair. During evolution, theprotein sequences encoded in our DNA have been optimised for thesefunctions.

The reliable folding of proteins is a prerequisite forthem to function robustly. Mis-folding can lead to protein aggregatesthat cause severe diseases, such as Alzheimer's, Parkinson's, or thevariant Creutzfeldt-Jakob disease. To understand protein folding,research has long focused on metastable folding intermediates, whichwere thought to guide the unfolded protein chain into its foldedstructure. It came as a surprise about a decade ago that certain smallproteins fold without any detectable intermediates. This astonishinglydirect folding from the unfolded state into the folded state has beentermed ‘two-state folding’. In the past few years, scientists haveshown that the majority of small single-domain proteins are ‘two-statefolders’, which are now a new paradigm in protein folding.

Thecharacteristic event of two-state folding is the crossing of a barrierbetween the unfolded and folded state. This folding barrier is thoughtto consist of a large number of extremely short-lived transition statestructures. Each of these structures is partially folded and willeither complete the folding process, or will unfold again, with equalprobability. Transition state structures are thus similar to a ball ona saddle point, which has the same probability, 0.5, of rolling toeither side of the saddle.

Since transition state structures arehighly instable, they cannot be observed directly. To explore two-statefolding, experimentalists instead create mutants of a protein. Themutants typically differ from the original protein -- the wild type --in just a single amino acid. The majority of these mutants still foldinto the same structure, however the mutations may slightly change thetransition state barrier and, thus the folding time; that is, the timean unfolding protein chain on average needs to cross the foldingbarrier.

The central question is: can we reconstruct thetransition state from the observed changes in the folding times? Such areconstruction clearly requires experimental data on a large number ofmutants. In the traditional interpretation, the structural informationis extracted for each mutation, independent of the other mutations. Ifa mutation does not change the folding time, then the mutated aminoacid traditionally is interpreted to be still unstructured in thetransition state. In contrast, if a mutation changes the folding time,the mutated amino acid is interpreted to be partially or fullystructured in the transition state, depending on the magnitude of thechange.

This traditional interpretation is however often notconsistent. For example, twenty single-residue mutations in the α-helixof the protein Chymotrypsin Inhibitor 2 (CI2) have very differenteffects on the folding time. Naοvely interpreted, these differencesseem to indicate that some of the helical residues are unstructured inthe transition state, while other residues, often direct neighbours,are highly structured. This naοve interpretation contradicts the factthat the folding of helices is co-operative, and can only occur ifseveral consecutive helical turns are structured, stabilizing eachother.

In a recent article in PNAS, a research team from the MaxPlanck Institute of Colloids and Interfaces and the University ofCalifornia, San Francisco has suggested a novel interpretation of themutational data. Instead of considering each mutation on its own, thenew interpretation collectively considers all mutations within acooperative substructure, such as a helix. In case of the α-helix ofthe protein CI2, this leads to a structurally consistent picture, inwhich the helix is fully formed in the transition state, but has notyet formed significant interactions with the β-sheet.

In thefuture, the Max Planck researchers hope to construct completetransition states from mutational data. An important step is toidentify the cooperative subunits of proteins, which requires molecularmodelling. In a similar way to how a mountain pass shows us how tocross the landscape, the transition states eventually may help us tounderstand how proteins navigate from the unfolded into the foldedstructure.

Story Source:

The above story is based on materials provided by Max-Planck-Gesellschaft. Note: Materials may be edited for content and length.

Cite This Page:

Max-Planck-Gesellschaft. "What Mutations Tell Us About Protein Folding." ScienceDaily. ScienceDaily, 17 October 2005. <www.sciencedaily.com/releases/2005/10/051015092546.htm>.
Max-Planck-Gesellschaft. (2005, October 17). What Mutations Tell Us About Protein Folding. ScienceDaily. Retrieved October 23, 2014 from www.sciencedaily.com/releases/2005/10/051015092546.htm
Max-Planck-Gesellschaft. "What Mutations Tell Us About Protein Folding." ScienceDaily. www.sciencedaily.com/releases/2005/10/051015092546.htm (accessed October 23, 2014).

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