New technique invented by EMBL researchers reveals uncharted docking sites in RNA-binding proteins
Some proteins are less like landlines and more like smartphones: they can do more than just talk to other proteins. One molecular app of particular interest is the ‘RNA-binding domain’, which lets proteins engage with RNA and influence how a cell responds to its environment. Lots of proteins use it – even ones that do not appear to have one. So how do you find an app that is clearly in use but has an invisible launch site? Researchers at EMBL invented a technique to do just that. Called RBDmap, the new method was recently published in Molecular Cell.
“We are one step closer to understanding how RNA and proteins interact,” says Matthias Hentze, who led the study.
Decades of research in the RNA field confirmed that proteins of a certain architecture can bind to RNA. But when the Hentze lab systematically searched for proteins that are able to bind to RNA using next generation methods, they saw something surprising: many of the proteins they discovered did not have any signature that could explain their RNA-binding ability. And yet, these enigmRBPs – as they came to be called – could still bind to RNA. But how? And why?
We are one step closer to understanding how RNA and proteins interact
In order to answer these questions, the EMBL scientists first needed to figure out which part of these enigmatic proteins does the binding in the first place. That’s where RBDmap comes in.
Think of RNA-binding proteins as people holding onto a single rope – a strand of RNA. The hands holding the rope represent the part of the protein that can interact with RNA, while the rest of the body is free to do something else. “RBDmap separates the hands from the rest of the body and identifies what these hands are and to whom they belong,” explains Alfredo Castello, who developed the technique as a staff scientist in Hentze’s lab. “It tells us exactly what part of the protein binds to RNA.”
Using this new approach, Hentze, Castello and colleagues mapped over one thousand previously unrecognised RNA-binding sites within 529 proteins. With this information, the researchers look forward to investigating how these RNA-binding proteins work. “If we can change a very small part of the protein, chances are it can no longer bind to RNA,” Hentze said. “But, the protein can still do its other jobs – which may be vital for the cell’s survival,” Hentze said. From these mutations, the researchers can begin to investigate the role of RNA binding in how cells respond to physiological stresses such as starvation and disease.
Castello is presently leading his own lab at the University of Oxford.