One Protein - Two Folds

Michael Clarkson at Discount Thoughts posted a discussion of a paper published by Tuinistra et al. (2008) [Two folds for lymphotactin]. The interesting thing about this paper is that it describes a protein (the chemokine lymphotactin) that can adopt two very different folds under physiological conditions.

This is an exception to the general principle that a protein will adopt a single thermodynamically stable three-dimensional structure. Here's how Micheal Clarkson describes it ... (Please read his article.)
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This is an interesting and important finding because it is (so far) the only example of a protein adopting two completely different stable folds with no hydrogen bonds in common at equilibrium. Trivially, natively disordered proteins adopt multiple conformations under physiological solution conditions, and many proteins alter their conformations in response to ligand binding while keeping most of their hydrogen bond network intact. In this case, however, an existing network of stabilizing bonds is completely disrupted in order to form a new fold with a totally different function. I've already discussed some of the implications of this with respect to protein folding, and in regards to the recent transitive homology studies out of the Cordes group. Lymphotactin offers lessons and ideas for protein folding and evolution that must be taken into account. In particular, the fact that point mutations can significantly stabilize one or the other of these structures implies that there may be previously unsuspected shortcuts through structural space between folded states that avoid unproductive or energetically unfavorable molten globules.

In addition, these results signify that the Anfinsen paradigm that dominates our understanding of protein structure ought not be taken for granted.¹ In many cases it is true that a peptide sequence uniquely determines a single structure under all physiological conditions. Of course we have known for some time that certain peptide sequences do not produce ordered structural ensembles at all. What the lymphotactin example makes crystal clear is that a given sequence can yield an ensemble with multiple energetic minima that reflect related but topologically distinct structures. Tuinstra et al. suspect that this phenomenon has not been noted previously because structures of this kind would not be amenable to crystallization, or would only crystallize in one (of many) structures. If this is so, then as more and more proteins are studied using solution techniques under physiological conditions we may find multiple structural minima in a variety of proteins. Such discoveries may significantly enhance our understanding of the protein regulation, function, and evolution.

Why is this important? Because this example demonstrates that getting from one type of fold to another type of fold isn't as big a problem as most people think.

The key phrase in Michael Clarkson's explanation is, "In particular, the fact that point mutations can significantly stabilize one or the other of these structures implies that there may be previously unsuspected shortcuts through structural space between folded states that avoid unproductive or energetically unfavorable molten globules." As we will see, the Intelligent Design Creationists argue that it is impossible to evolve from one type of protein to another, therefore God must have done it.

Incidentally, it's worth noting that some proteins adopt different conformations when they bind to other molecules (the target they bind to is called a "ligand" and it could be DNA, another protein, or a small molecule like ATP). Michael Clarkson mentions this—he appears to be a pretty knowledgeable guy—but I just want to repeat it so that everyone understands. The idea that parts of a protein (motifs, domain) can change folds under certain conditions isn't new.

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1. I would prefer to say that, like all general concepts in biology, there are exception to the Anfinsen paradigm. I don't believe there are any fundamental concepts that don't have exceptions. That's the nature of biology, and evolution.

Tuinstra, R.L., Peterson, F.C., Kutlesa, S., Elgin, E.S., Kron, M.A., and Volkman, B.F. (2008) Interconversion between two unrelated protein folds in the lymphotactin native state. Proc. Nat. Acad. Sci. (USA) 105:5057-5062. [doi: 10.1073/pnas.0709518105]