It is possible to understand a significant number of
interactions among human proteins from the evolution of their
counterparts in simpler cells, such as bacteria cells, suggests a new study published in
the journal Proceedings of the National Academy of Sciences (PNAS).
Cells operate like an incredibly well-synchronized orchestra of molecular interactions among proteins. Understanding this molecular network is essential not only to understand how an organism works but also to determine the molecular mechanisms responsible for a multitude of diseases.
In fact, it has been observed that protein interacting regions are preferentially mutated in tumors. The investigation of many of these interactions is challenging. However, a study coordinated by Simone Marsili and David Juan, from Alfonso Valencia's team at the CNIO, will advance our knowledge on thousands of them.
However, out of 200,000 protein-protein interactions estimated, only a few thousand have been characterized at the molecular level". It is very difficult to study the molecular properties of many important interactions without reliable structural information. It is this "twilight zone" that, for the first time, CNIO researchers have managed to explore.
FROM BACTERIA TO HUMANS TO UNDERSTAND DISEASES
Although more than 3,000 million years of evolution separate bacteria and humans, the CNIO team has utilized the information accumulated over thousands of bacterial sequences to predict interactions between proteins in humans. "We have used the protein coevolution phenomenon: proteins that interact tend to experience coordinated evolutionary changes that maintain the interaction despite the accumulation of mutations over time," says David Juan.
"We have demonstrated that we can use this phenomenon to detect molecular details of interactions in humans that we share with very distant species. What is most interesting is that this allows us to transfer information from bacteria in order to study interactions in humans that we knew almost nothing about," adds Simone Marsili.
These new results may lead to important implications for future research. "A deeper understanding of these interactions opens the door to the modeling of three-dimensional structures that may help us to design drugs targeting important interactions in various types of cancer," explains David Juan. "This knowledge can also improve our predictions of the effects of various mutations linked to tumor development," says Rodríguez.
The laboratory of Alfonso Valencia, head of the Structural Biology and Biocomputing Programme, has been working in the field of protein coevolution since the 1990s. This field has significantly advanced in recent years. "Thanks to the amount of biological data that is being generated today, we can use new computational methods that take into account a greater number of factors," explains Valencia.
According to the researchers, the pace of innovation in massive experimental techniques is providing additional data, making it possible to design more complex statistical models that provide an ever more complete view of the biological systems, "something particularly important in multifactorial diseases, such as cancer."
This work was supported by the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund.