Complete changes from one type of living thing to another have been the stuff of fiction: Dr. Jekyll’s transformation to Mr. Hyde (and back) and Franz Kafka’s Metamorphosis spring to mind. But researchers at Universität Bayreuth and Ohio State University discovered that these dramatic structural and functional transformations do occur in molecules deemed least likely to change; proteins. Their study appears in the July 20 issue of the journal Cell.
Proteins form the structures of all living things. They also aid in such crucial functions as transmitting genetic information or enabling cells to consume (and produce) energy. Proteins’ intricate structures are meticulously regulated by genes. These 3-D arrangement of folds, twists and shapes determine how proteins work, much as a hammer’s shape allows a different function from a screwdriver’s. Any variation in a protein’s structure can drastically alter how it works, often resulting in disease or death. And each protein is custom-designed for each task.
Or so we thought. The researcher’s discovery–that a protein can function in one form, transform itself, and then function in a completely different form–was a shock. “A complete fold conversion is the last idea you would typically consider—it is too wild,” said Irina Artsimovitch, one of the study’s leaders. “You would think this is impossible. That’s what you’re told in school.”
Classical genetics teaches us that DNA uses proteins to regulate production of mRNA, which provides a template for creating proteins. Another type of RNA, called tRNA, then uses the template to assemble proteins block by block. The “blocks” in proteins are amino acids, and tRNA arranges them in precise order to ensure every protein assumes a specific shape and function.
The group discovered that the protein RfaH, which helps bacteria attack host organisms more aggressively, could refold itself and adopt entirely different functions. The protein has two shapes: an “alpha” spiral shape, and a “beta” shape that resembled a hub and spokes on a wheel. The alpha form of RfaH ensured that DNA produced mRNA. But RfaH then transformed into the beta shape, abandoning its previous function. In its new conformation, beta RfaH could actually move down the assembly line and make the proteins block by block. No protein has ever been seen doing this.
The study blasts assumptions of how proteins work and cause disease when they don’t. The RfaH protein is, in evolutionary terms, a very old one, found in every living cell. If RfaH and other proteins can refold and retool themselves, then many other proteins can bind together and affect cellular processes in ways that hadn’t been imagined before.
For example, prion proteins, which are linked to several disorders including Bovine Spongiform Encephalopathy (“Mad Cow” disease) and Creutzfeldt-Jakob disease, may owe their lethal effectiveness to this refolding. Not much is known about the exact structural changes undergone by prions, but this and similar studies may shed more light.
Burmann BM, Knauer SH, Sevostyanova A, Schweimer K, Mooney RA, Landick R, Artsimovitch I, & Rösch P (2012). An α Helix to β Barrel Domain Switch Transforms the Transcription Factor RfaH into a Translation Factor. Cell, 150 (2), 291-303 PMID: 22817892
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