For most proteins, structure is function. The complex three-dimensional shapes that proteins adopt create folds and pockets that can accomplish the extraordinary improbable: drive chemical reactions that would otherwise never occur or bind to a single chemical in the complex environment of a cell. Protein structure is so important that there is an entire discipline with many well-developed approaches to figuring out what a protein looks like when it is folded into its active state.
But that’s just mostly protein. Scientists have also discovered a growing catalog of intrinsically disordered proteins. Rather than having a fixed structure, intrinsically disordered proteins appear to have whole segments that flutter in the gusts of Brownian motion and are, nevertheless, crucial to the protein’s structure. People aren’t sure if these proteins have temporarily adopted a specific conformation to function, or if the disorder is critical to function.
Now, a new paper describes a case where two intrinsically disordered proteins interact with each other to form specific structures. And Google’s new AlphaFold AI software was instrumental in discovering this structure.
Chasing disorder
Most studies of protein structures identify amino acid positions with a high degree of certainty. However, many proteins had regions where these studies produced equivalent opacity, suggesting that part of the protein is in constant motion in the environment. Many additional proteins also completely defy structural studies.
For many years, these were considered oddities that had little to do with each other. Eventually, people came to the idea that these apparently disordered states were not an experimental artifact, but rather represented the actual behavior of proteins—and, in some cases, were essential to their function. A major conceptual advance was the idea of intrinsically disordered proteins.
Since then, researchers have identified several ways these things work. In some cases, they can form a specific structure when interacting with a different molecule. In others, they allow different structures to form depending on which molecule they are interacting with. In others, proteins remain disordered even when they are functionally active. Determining which is the case for a given intrinsically disordered protein can be a serious challenge.
But this is the challenge that a group of researchers from Hefei, China decided to tackle. They were interested in a protein called protein 4.1G, which interacts with a protein called NuMA, which is essential for cell division. The regions of both NuMA and protein 4.1G that mediate this interaction have been identified, and both are intrinsically disordered.
So how do you figure out what the protein is doing?