UNEXPECTED SHEET Credit: Nature

Intrinsically 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 stabilizes the β-sheet domain, locking it into 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.”

They 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.

Sign up for C&EN's must-read weekly newsletter Email Address * Subscribe » Contact us to opt out anytime