In the old days when protein pretty much meant enzyme, heating them caused loss of their catalytic activity (e.g. denatured them). A more familiar example is what happens when you boil an egg — the albumin in the egg white turns into a solid (delicious) mass.
Now that we know a bit more about protein structure, it was clear what was going on when an enzyme was denatured. Consider a typical serine protease with its catalytic triad of 3 amino acids (aspartic acid, histidine, serene) which have to be correctly juxtaposed in 3 dimensional space for the enzyme to work. However, in a typical enzyme, aspartic acid is 45 amino acids away from histidine on the linear protein chain. Serine is even farther away 92 amino acids and in the other direction to boot. Heating the protein causes the chains to contain more kinetic energy, the protein chain (polypeptide backbone if you’re fancy) flops around, and the 3 amino acids separate from each other, and in the case of albumin, they never find their way back.
So denaturation came to be associated with the idea of an unstructured protein (meaning really a protein with multiple structures changing into each other all the time). For more details on this see http://luysii.wordpress.com/2010/08/04/why-should-a-protein-have-just-one-shape-or-any-shape-for-that-matter/ and http://luysii.wordpress.com/2010/10/24/the-essential-strangeness-of-the-proteins-that-make-us-up/. I find it nothing short of miraculous that the proteins making us up have just a few 3 dimensional shapes (conformations of the protein backbone), e.g. that any protein is structured at all. The two links will tell you why I think this way.
However some bacteria have a protein which functions in this disordered state. It’s called HdeA and it is found between the two layers of the cell membrane in Gram negative bacteria such as E. Coli and Shigella. The region between the two layers of the membrane is called the periplasm. The outer membrane is quite leaky, so when an animal ingests the bacterium, it is exposed to the acid conditions in the stomach (which can be as concentrated as 1 MOLAR HCl (e.g. pH = 1). This causes most normal proteins to ‘denature’ — e.g. lose their 3 dimensional shape and become unstructured.
Enter HdeA, which has a nice shape and forms a dimer at physiologic pH (e.g. around 7). When exposed to acid, the dimer splits apart and the protein becomes ‘unstructured’ — but certainly not denatured in the old sense, because it is the unstructured form of HdeA which is functional. It serves as a molecular chaperone, using its floppy protein backbone, to bind and protect other proteins which have become unstructured due to the acid pH. Amusing no? Anything not expressly forbidden, must occur (Gell-Mann on particle physics on the way to discovering the 8fold way)
Here are a few references and some gory details for the aficionado.
[ Proc. Natl. Acad. Sci. vol. 106 pp. 5557 - 5562 '09 ] HdeA is a bacterial chaperone protein found in the periplasm which is activated by pH’s under 3 (which the ingested bacteria find themselves in as soon as they hit the stomach, because the outer membrane of gram negatives is permeable to molecules smaller than 600 Daltons). It is one of the smallest chaperones known (mass 9.7 kiloDaltons). HdeA undergoes an acid-induced dimer to monomer transition. It functions as a disordered monomer without the need for ATP. Activation exposes the hydrophobic dimer interface which is critical for substrate binding). The partially unfolded character of active HdeA allows the chaperone to adopt different conformations as required for recognition and high affinity binding of different substrate proteins. So the disordered state is crucial to function and one can’t equate disordered with denatured.
[ Proc. Natl. Acad. Sci. vol. 107 pp. 1071 - 1076 '10 ] Most molecular chaperones are either ATP dependent or rely heavily on their ATP dependent chaperone counterparts (??) to promote protein folding. There is no ATP in the bacterial periplasm which is permeable to the outside. However, there is a chaperone there in E. Coli and Shigella called HdeA. It binds to substrates at low pH (preventing aggregation). When pH is neutralized, the proteins are released. Unfolding and dissociation of HdeA into monomers caused by low pH, actually activates is chaperone function by inducing the exposure of structurally plastic, high affinity binding sites for unfolding proteins on HedA, allowing it to prevent protein aggregation. Partially unfolded HdeA monomers are quite flexible, allowing it to bind to a variety of substrates, some of which are much larger than the 9.7 kiloDalton HdeA itself. Inactivation of HdeA is triggered by pH neutralization, which induces its refolding and dimerization.
Next up, two background posts and then a longer post on the most interesting paper I’ve read in the past 5 years.