2023-04-16 15:04:40
Proteins are key players in virtually all molecular processes within the cell. To perform their various functions, they must interact with other proteins. These protein-protein interactions are mediated by highly complementary surfaces, which typically involve many amino acids that are precisely positioned to produce a tight, specific fit between two proteins. However, relatively little is known regarding how these interactions are created during evolution.
The classical theory of evolution suggests that any new biological feature involving many components (such as amino acids that allow interaction between proteins) evolves gradually. According to this concept, every small functional improvement is driven by the power of natural selection, because there is a benefit associated with functionality. However, whether protein-protein interactions also always follow this trajectory was not fully known.
Using a highly interdisciplinary approach, an international team led by Max Planck researcher Georg Hochberg of Marburg Terrestrial Microbiology has now shed new light on this question. Their study provides definitive evidence that highly complementary and biologically relevant protein-protein interactions can evolve entirely by chance.
Proteins cooperate in a photoprotection system
The research team made their discovery in a biochemical system that microbes use to adapt to stressful light conditions. Cyanobacteria use sunlight to produce their own food through photosynthesis. Because a lot of light damages the cell, cyanobacteria have evolved a mechanism known as photoprotection: if light intensities get dangerously high, a light intensity sensor called orange carotenoid protein (OCP) changes shape. In this activated form, OCP protects the cell by converting excess light energy into harmless heat. To return to their original state, some OCPs depend on a second protein: Fluorescence Recovery Protein (FRP) binds to activated OCP1 and greatly accelerates its recovery.
“Our question was: is it possible that the surfaces that allow these two proteins to form a complex evolved entirely by accident, rather than direct natural selection? said Georg Hochberg. “The difficulty is that the end result of both processes looks the same, so we usually can’t tell why the amino acids needed for an interaction evolved – by natural selection for the interaction or by chance. To tell them apart, we would need a time machine to witness the exact moment in history when these mutations occurred,” explains Georg Hochberg.
Fortunately, recent breakthroughs in molecular and computational biology have equipped Georg Hochberg and his team with a kind of time machine laboratory: the reconstruction of ancestral sequences. Moreover, the light protection system of cyanobacteria, which has been studied in the group of Thomas Friedrich of the Technische Universität Berlin for many years, is ideal for studying the evolutionary encounter of two protein components. The first cyanobacteria acquired the FRP proteins from a proteobacterium by horizontal gene transfer. The latter itself had no photosynthetic capacity and did not possess the OCP protein.
To understand how the interaction between OCP1 and FRP evolved, graduate student Niklas Steube deduced the sequences of ancient OCPs and FRPs that existed billions of years ago in the past, then resurrected them in the lab. After translating the amino acid sequences into DNA, he produced them using E. coli bacterial cells in order to study their molecular properties.
A happy coincidence
The Berlin team then tested whether ancient molecules might form an interaction. This way, the scientists were able to trace how the two protein partners got to know each other. “Amazingly, the FRP of proteobacteria already matched the ancestral OCP of cyanobacteria, even before gene transfer took place. The mutual compatibility of FRP and OCP has therefore evolved completely independently of each other in different species, explains Thomas Friedrich. This allowed the team to prove that their ability to interact must have been a happy accident: selection might not have plausibly shaped the surfaces of the two proteins to allow interaction if they had never met. This ultimately proved that such interactions can evolve entirely without direct selective pressure.
“It may seem like an extraordinary coincidence,” says Niklas Steube. “Imagine an alien spacecraft landing on earth and we discover that it contained plug-shaped objects that fit perfectly into man-made sockets. But despite the perceived improbability, such coincidences might be relatively common. But in fact, proteins often encounter a large number of new potential interaction partners when localization or expression patterns change in the cell, or when new proteins enter the cell by horizontal gene transfer. Georg Hochberg adds: “Even if only a small fraction of these encounters end up being productive, chance compatibility may underlie a significant fraction of all the interactions we see inside cells today. Thus, as in human partnerships, a good evolutionary match might be the result of a chance meeting of two already compatible partners.
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