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.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.
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.
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.
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]
3 comments :
Thanks for your kind words, Larry. The point I was trying to make with the statement about Anfinsen was that a number of major projects rely on this idea implicitly. Obviously structural genomics projects have this idea in mind, but so do large-scale protein fold prediction efforts like CASP. These efforts rely on the idea that context is largely irrelevant to conformation, accepting that this will lead to undersampling of the ensemble in proteins where ligands or ions cause some rearrangements (Adenylate kinase, for example). Lymphotactin demonstrates that these omissions may be more significant to function than previously believed.
Have you seen this upcoming paper in PNAS Larry?:
"Detecting evolutionary relationships across existing fold space, using sequence order-independent profile–profile alignments"
http://www.pnas.org/cgi/content/abstract/0704422105v1
Looks interesting to me. For those of us who aren't experts in this area, I particularly appreciated the intro, which gave some nice background info:
Comparative genomics studies and structural and phylogenetic analyses (8–10) have established that a subset of proteins, dominated by the structure classification of proteins (SCOP) (11) / class, , were likely present in the last universal common ancestor (12, 13). Concurrently, growing evidence suggests that recurring substructures, that is, 3D fragments of noncontiguous sequence shared between different folds, may be clues that protein fold space is more continuous than discreet (14, 15). The sequence/
structure similarity of such substructures correlates well with the similarity of function found between the different folds containing these substructures (16). The notion that protein fold space is a continuum is further supported by recent studies that show that protein domains can adopt different topologies through
combination, swapping, deletion (4, 17, 18), and cyclic permutation
(19, 20) of subdomains. Likewise, new folds can emerge from accretion (21) or embellishment (22) of substructures around a core of conserved secondary structures.
The prion protein PrP scrapie also adopts two very distinct folds with the same primary sequence.
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