The Funny Thing about Protein Folding

Proteins are strung together from amino acids attached in long chains, one after the other. But for most proteins, this is just the beginning - next they must fold. "Folding" is the general term for the way that a protein strand twists, coils, winds, pleats and creases into an intricate three-dimensional structure. Only then can it go to work.

The sequence of amino acids is what determines the final shape of the protein: Molecules assembled on the same plan will end up in the exact same configuration. The funny thing is, they don't all go through the same set of steps to arrive at their final structure. Some of them, apparently, take shortcuts. It's as if you could skip a few steps in the origami instructions and still end up with a perfect paper crane in the end.

To observe and compare how individual protein strands fold, the Weizmann Institute's Prof. Gilad Haran and his team had to invent some new techniques, including fluorescent microscopy methods and data analysis that enabled them to collate thousands of individual events into a timeline of protein folding.

Haran_molecular landscape.png
Experiments revealed multiple possible "paths" through a protein's folding landscape

The team identified six different intermediate configurations for the protein they studied. Sometimes the strands went through all of them; other times, they took an easier, shorter route to their final form.

Why would a molecule go through extra contortions to get to the same state? The findings contain a clue: The process became longer and more tortuous in the presence of some external factors such as heat or higher concentrations of certain chemicals in the protein's environment.

Like much good research, this study raises more questions than it answers: Is this a general rule that holds for different types of proteins? What advantages do the different routes to protein structure confer? How this might tie into such disorders as Alzheimer's disease, in which badly-folded proteins form plaques in brain tissue?

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Really interesting. I think that has something to do with evolutionary mechanism. Maybe it's a way of acting that was a 'basic way' in past?

Is this a general rule that holds for different types of proteins?

My protein folding textbook from the 1980s says yes.

Is this a general rule that holds for different types of proteins? Science writer's simplification. Assuming that the order of conformational changes is not random, the idea is to map the various routes in detail, infer a set of rules and see which ones can be applied to other classes of proteins. (If this is in your textbook from the 1980s, we would be interested in seeing it.)

I partially agree with Weizmann Science Writer but the main point here is who will infer these set of rules? Every genius/author has his prospective so whose right and whose not. Bill raised a great question from 1980s to 2010s and from 2010s to 2030s prospective will change again.

PROTEIN FOLDING:Deciphering the second half of the Genetic Code (1989) Gierash & King, eds. AAAS, ISBN 0-87168-353-9

From the Nature Communications article:

"Many smFRET protein folding experiments have been performed on freely diffusing molecules, and have revealed fascinating details on phenomena such as the collapse transition or the nanosecond chain reconfiguration dynamics in the denatured state. However, experiments on freely diffusing molecules are limited to short time scales, of the order of a millisecond, and some form of immobilization is required to study dynamics on longer time scales. Only a handful smFRET folding experiments have been performed on immobilized molecules. The promise of this type of experiment to identify intermediates in the folding of large proteins and characterize the pathways connecting them has yet to be fulfilled."

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