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Defying Dogma, Researchers Hail Unfolded Proteins

SAN DIEGO, June 6 - A sizable contingent of researchers are working to uncover the rules of protein folding, but a growing number of scientists believes unfolded proteins may be just as important.


"Not all proteins are the nice three-dimensional structures we are used to seeing; many functional proteins are intrinsically unstructured," Peter Wright, chairman of molecular biology at The Scripps Research Institute, said during a "protein disorder" session here at the Beyond Genomes conference. "This is a major challenge of structural biology and genomics."


This is the first time the conference has held a protein-disorder track. The change can be traced to the critical mass of new data that points to the prevalence and importance of unstructured proteins, said Keith Dunker, the session chair and professor of biochemistry and biophysics at Washington State University.


The proteins comprising eukaryotes have large disordered, or unfolded, regions in more than half of their proteomes, said Zoran Obradovic, director of Temple University's Center for Information Science and Technology, and a speaker at the conference.


These proteins are in a state other than the classic 3D structure believed by many researchers to be necessary for the "lock and key" model of protein interaction, explained Dunker. Instead, these protein sections may be completely unfolded, partly folded, momentarily folded, or in a state somewhere in between though still able to interact and regulate a cell's function.


They also fail to show up on the Protein Data Bank--inclusion in the database "is predicated on having a known structure," said Dunker. But that doesn't mean they have gone unnoticed.


"People who focus on protein structure for a living know of examples," Dunker explained. "But most don't know how common they are."


Additionally, researchers who encounter them during experiments may discount the results as errors and purge them from reports and papers, he said.


But it's "getting to the point where people can't ignore this anymore. This is taking off because bioinformatics suggests that half of our proteins have disordered regions."


Many researchers who sat in on the protein disorder presentations came away talking.


"Now we learn that the idea of a random coil is not really random [but] one of the basic structures of protein," said Christine Lemke, chief operating officer of German-based MelTec. "It's a new layer of information; it adds complexity."


And it may add a new twist--or untwist--to drug development.


"The common textbook [interpretation] is protein fields are in a three-dimensional structure and the purpose is to position in space to carry out molecular recognition," said Dunker. "That 3D structure equals function is viewed as a prerequisite. But proteins partially folded, or disordered, can also carry out molecular recognition. They do fold into 3D, but do binding and folding at the same time, not separately. If you have this simultaneous binding and folding, you can have weak as well as strong reactions. In biology, this allows signaling."


And proteins rich in this type of signaling conformation may be prevalent in cancer signaling, he said.


"Understanding molecules in disordered regions will [help develop] new cancer drugs more successful than those around now," predicts Dunker.


To accumulate a larger sample of these proteins and put them on the radar of a broader range of researchers, Dunker is "bootstrapping" a disordered protein database that he will soon submit for funding to the National Science Foundation.


"It's a start," he said.