Academic journal article The American Biology Teacher

Unfolding Proteins

Academic journal article The American Biology Teacher

Unfolding Proteins

Article excerpt

Most of us have to teach about protein structure. We know the drill: primary structure being the linear sequence of amino acids, secondary involving the folding of portions of this chain into an alpha helix or beta pleated sheet. Then comes tertiary, where these segments and the sequences linking them are further folded into less regular and more complex forms. Finally, for proteins made up of several chains, there is a further level of structure, the quaternary, describing how these subunits come together to form the full molecule. I can remember learning this more than 40 years ago, so this hierarchy has been around a long time, though the number of examples of each structural level has grown tremendously since then. In the 1960s, only a few proteins had been sequenced and even fewer had been worked out structurally. But the basics were known even "back then." This makes it even more surprising that there is growing evidence that some proteins just don't behave well, don't have a defined structure beyond the primary

In an article entitled "Breaking the Protein Rules," Tanguy Chouard (2011) describes research on proteins that seem to be either totally or partially disordered. With a bioinformatics computer program that analyzes protein sequence data, Keith Dunker of Indiana University has found that about 40% of human proteins have some disordered segments of 30 amino acids or more; for about 25%, the entire molecule is disordered. This seems pretty startling--and in fact, many structural biologists don't believe this analysis. While they admit that small segments of a protein may be at least partially disordered, this is usually only when it is active, changing shape to bind a ligand.

In defense of his research, Dunker argues that his results seem surprising because disordered proteins don't crystallize, and thus their structures can't be easily studied. These are the proteins that aren't tackled by structural biologists. However, improvements in nuclear magnetic resonance (NMR) spectroscopy are making it possible to determine the form of small proteins, even if they are twisting and turning in solution. Such studies suggest that disorder may actually be essential for some proteins' functioning; a shapeless segment can aid in a signaling protein's recognition of its protein partner or help a regulatory protein interact with more than one target. This is a far cry from the lock-and-key model of protein binding that we all learned, a metaphor that implies a specific shape fitting into another specific form. In the case of a portion of the gene-regulatory protein CREB, it only takes on its lock-like form when it comes in contact with the "key" to which it binds. There is even a signaling protein called Sic1 that stays disordered even when bound to its receptor. It has six phosphate groups, and each occupies the binding site in turn: think of a writhing snake with different parts of its body making contact with a surface.

It's still not at all clear how common such phenomena are, but they are fascinating and suggest that perhaps Dunker and his associates are correct, that things are not nearly as ordered in the protein world as many biologists had thought. Obviously, the debate between the disorder advocates and opponents will continue until more hard evidence replaces computer modeling. In all likelihood, both sides will prove to be partially correct. Mentioning this controversy could spice up a presentation on protein structure, which is definitely a topic that could use some spice. Structure on top of structure can seem very daunting to a student who is still trying to make sense of peptide bonds.

** Doing It Differently

Another long-held tenet of protein structure is also being questioned: the idea that a protein has a unique structure determined by its amino acid sequence. This concept is usually introduced with the story of Christian Anfinsen heating a solution of ribonuclease until this enzyme unfolded, then allowing it to slowly cool, and finding that the protein folded back into its native state, without any other molecules involved. …

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