NEWS OF THE WEEK
PHOSPHORYLATION FOLDS FLOPPY PROTEIN STRUCTURAL BIOLOGY: Disordered
protein could be new drug target
I
NTRINSICALLY DISORDERED PROTEINS, which
lack a well-defined three-dimensional structure, typically fold up only when they bind their targets. But appending phosphate groups, a common protein modification, can be enough to make one of these floppy proteins fold on its own, a team led by Julie D. Forman-Kay of the University of Toronto reports (Nature 2014, DOI: 10.1038/nature13999). Forman-Kay’s team had studied phosphorylation in other disordered proteins but had never seen the modification cause a protein to fold. This time they focused on a disordered protein called 4E binding protein-2 (4E-BP2), which binds to a protein involved in translation and suppresses initiation of protein synthesis. When 4E-BP2 binds its target, part of it folds up into a small helix. Phosphorylation of two amino acids in 4E-BP2, however, causes the surrounding region to fold up into a β-sheet domain, blocking the formation of the helix. Phosphorylation at three other amino acids
A NEW LINK FOR ARYL POLYMERS POLYMER SCIENCE: Chemists have designed a direct method for preparing poly(o-arylene)s for the first time
C
Copper(I) catalyst
Aryne
HEMISTS IN JAPAN have developed the first
direct process for synthesizing poly(o-arylene)s, an achievement that provides new structural diversity to the polyphenylene class of polymers (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja5112207). Direct synthesis of poly(o-arylene)s has been missing from the aromatic chemistry tool kit for a long time. The n discovery of arynes, which are six-memPoly(o-arylene) bered rings containing a carbon-carbon triple bond, dates to 1902. Polyphenylenes in which aromatic rings are successively connected through the para and meta positions of the rings are known, but the ortho-linked versions had remained elusive. The ortho linkages give the polymers a different helical shape and will likely provide different stimulus-response behaviors than phenylenes linked through other CEN.ACS.ORG
10
NATUR E
Phosphorylation (red) of two amino acids causes 4E-BP2 to fold into a β-sheet domain, which blocks formation of a helix (green) needed for the protein to bind its target.
stabilizes the β-sheet domain, holding it in place. The resulting nonfunctional 4E-BP2 can’t bind its target. “People like to think that you need a fold for function, and if it’s disordered, a protein can’t be functional,” Forman-Kay says. In this case, the opposite is true: Only floppy, unphosphorylated 4E-BP2 can bind its target and influence translation. “That’s kind of fun because it turns the paradigm on its head.” The team analyzed 4E-BP2’s structure using nuclear magnetic resonance spectroscopy. Phosphorylation caused significant shifts in the NMR spectra of amide protons that are diagnostic of folding. Forman-Kay and her collaborators, particularly Nahum Sonenberg of McGill University, in Montreal, are now studying 4E-BP2 as a potential drug target for cancer, autism, and other neurological disorders. The researchers are screening for molecules that can stabilize or destabilize the β-sheet. “While 4E-BP2 was known to have a very powerful effect on the regulation of translation initiation, the fact that it can fold presents a completely new target,” Forman-Kay says. “This work represents a very important contribution to the intrinsically disordered protein field, providing a well-characterized example of a phosphorylationbased regulatory switch,” says Vladimir Uversky, an expert in intrinsically disordered proteins at the University of South Florida, in Tampa. “Since intrinsically disordered proteins are very promiscuous binders that are commonly phosphorylated, this mechanism could be widespread.”—CELIA ARNAUD
ring positions, the researchers believe. These properties are expected to open up new possibilities for developing nanocarbon materials for chiral catalysis and thin films for electronic devices and chemical sensors. Chemists indirectly made poly(o-arylene)s previously by polymerizing bicyclic alkenes and following up with a dehydration step. In the new work, Yoshihide Mizukoshi, Koichiro Mikami, and Masanobu Uchiyama of the University of Tokyo first treated an aryl trimethylsilyl triflate precursor with fluoride ion to generate an intermediate aryne. The polymerization was then mediated by a copper(I) reagent that directs ortho linkages, yielding poly(o-arylene)s up to 100 units long. “Considering the more than 100-year history of aryne chemistry and its formal resemblance to alkynes, it is rather strange that no one has ever succeeded in realizing addition polymerization of this highly reactive species,” says Eiji Ihara, a polymer chemist at Ehime University, in Japan, who has explored myriad potential ways to polymerize arynes. Ihara thinks the reason for the previous lack of success stems from arynes being too reactive for controlled polymerization, in contrast to olefins and alkynes, whose controlled polymerizations are well-established. “In that context, the achievement of Uchiyama’s group is quite significant, adding a totally new member to a family of monomers,” Ihara says.—STEVE RITTER
JANUARY 5, 2015
