Nearly two decades after the discovery of knotted proteins, most researchers think the strangely tangled molecules are too unwieldy to play much part in a cell’s activities.
This notion is changing. Researchers have discovered hundreds of complex knots in proteins. What appeared to be evolutionary cruft may prove useful.
"The knots are conserved across life, from bacteria to humans. They are doing something very important," said Joanna Sulkowska, a biophysicist at the University of California, San Diego. Sulkowska and Rice University biophysicist Jose Onechic led a knot discovery project described online this week in Proceedings of the National Academy of Sciences.
Biologists knew for decades that DNA strands could tie themselves into knots. But the first knotted protein wasn’t discovered until 1994 -- researchers assumed evolution had weeded them out.
"They thought the protein would spend too much time folding to do anything useful on molecular scales, that the landscape of a cell is too complicated to use knots," Sulkowska said.
The major challenge of working with any protein is verifying its actual structure. Computer models can hint at a functional form, but until a protein is isolated and scanned, it’s educated guesswork.
Knotted proteins are even more difficult to study, and traditional protein simulations struggle to predict the forms a knot might take.
Current algorithms used to understand proteins don’t even allow for the existence of knots.
To attack the modeling problem, Onuchic’s team developed a new algorithm to search for knots in more than 74,200 known protein sequences recorded in a massive database called the Protein Data Bank.
Their algorithm found 398 proteins with complex knots and 222 proteins with simple knots. What’s more, the knotted structures they discovered appeared in a wide array of life forms, from bacteria and plants to yeast and humans. Each branch of life seems to have found some way to make specific knots.
"This didn’t happen by accident. There has to be a reason, a function for these knots," Sulkowska said. "Now we can earnestly begin to ask this question."
Early results by other laboratories suggest that, in bacteria living around scalding-hot deep-sea hydrothermal vents, knots keep some proteins literally tied together. Other forms may play a role in afflictions such as Alzheimer’s disease, and perhaps even infectious diseases.
Sulkowska and colleagues are actively exploring the infectious disease angle now. Whether or not their own investigations pan out, Sulkowska expects knotted proteins to be proven important to life’s designs. "We use knots every day in the macroscopic world," she said. "The microscopic world should be no different."
Citation: "Conservation of complex knotting and slipknotting patterns in proteins” By Joanna I. Sułkowska, Eric J. Rawdon, Kenneth C. Millett, Jose N. Onuchic, and Andrzej Stasiak. PNAS, published online ahead of print. DOI: 10.1073/pnas.1205918109