Medicine is today produced to geometrically match the targeted biological molecules. Knowledge about how these molecules are structured is therefore essential for drug design and in getting the body’s molecules to communicate. In any case, this is what most people believed, until a combined research team from Denmark, Switzerland and the United States revealed the interaction between two natural proteins with no defined structure in the latest issue of Nature. Their finding calls for a rewriting of textbooks and a reconsideration of treatment strategies.
Having the wrong key for your cycle lock or the wrong PIN code for your mobile phone can cause great problems. The same is true when the body initiates processes. Correct interaction between the body’s molecules is required to ensure that the desired biological outcomes are achieved. However, the definition of what is required for a correct interaction has suddenly changed and Danish researchers are at the centre of the pioneering biological discovery.
“A dogma in biology has been that at least one of the proteins must have a well-defined structure to communicate with another protein. We have discovered two proteins that do not communicate with each other through a persistent, well-defined binding site but simply through a mean-field type of interaction between the large opposite charges of the two. This mechanism has never been seen before and rocks the foundations of the current understanding of how proteins of the body communicate,” explains Birthe B. Kragelund, Department of Biology, University of Copenhagen, a co-author of the article published in the prestigious journal Nature.
Highly dynamic
Initially, the researchers were attempting to understand the interaction between two proteins that are important for how our cells fold the genome such that it is compact when unused, while remaining easy to access when needed. One protein, histone H1 (H1), helps to fold the DNA, while the protein prothymosin-α (ProTα) pulls away H1 so the DNA can unfold.
“Their amino acid sequences suggested that both proteins were highly, but oppositely charged. We were therefore interested in determining how they interacted. However, when we tried to determine their binding sites, we saw that both proteins remained unstructured and dynamic.”
This dynamic complex caused the researchers to examine the associations of the proteins in greater detail using three advanced visualization techniques: single-molecule fluorescence spectroscopy, which enables researchers to study the dynamics of large biological molecules; nuclear magnetic resonance (NMR) spectroscopy, which enables researchers to reveal the details of the binding sites; and computer simulation, which allows theoretically computation and visualization of the interaction.
“Showing that two proteins have a specific way of interacting is easier than proving that there is definitely no long-lasting interaction. However, by using this arsenal of complementary methods, we ascertained that these two proteins had no fixed binding sites. You should imagine two continuously dynamic molecules that only interact by virtue of their charge properties.”
Looking through too narrow a lens
The researchers’ new results have really rocked the foundations of biology. Previously, researchers had found examples of unstructured proteins that could communicate – but always with a structured protein, and typically resulting in the unstructured protein acquiring a specific shape through the interaction. However, the new interaction mechanism is likely not a unique case, say the researchers.
“We have scanned the human genome, and there are a lot of proteins with comparable sequences which may potentially engage in similar complexes. This is naturally something we must now prove. The reason why this phenomenon has not been discovered before is presumably because we were locked into one way of viewing proteins. We were simply looking through too narrow a lens.”
The researchers must therefore rethink their view of interactions between proteins, since charged interactions should generally be assumed to play an important role in the dynamics between large biological molecules. This knowledge is not just important for understanding biology but also for treating diseases, which now must include expanded design principles.
“This kind of discovery often produces more questions than answers, and this reminds us how little we really know, because we normally operate within known paradigms. Our discovery has opened up a completely new area and thereby also potentially new opportunities for treating diseases if we can discover how to design medicines that can be targeted specifically through their charge.”
Extreme disorder in an ultrahigh-affinity protein complex” has been published in Nature. In 2016, Birthe B. Kragelund received funding under the Novo Nordisk Foundation Interdisciplinary Synergy Programme for the project Synergy – Investigating the Potential of the Protein–Membrane Co-structural Dynamics as a New Therapeutic Avenue. Birthe B. Kragelund leads the Structural Biology and NMR Laboratory (SBiNLab) at the Department of Biology, University of Copenhagen and focuses on studying dynamic complexes with NMR spectroscopy.
