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
‘Studying the evolution of thousands of bacterial proteins allows deciphering many interactions between human proteins. The results will help clarify the molecular details of interactions involved in 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.
According to Juan Rodríguez, from the Structural Computational
Biology Group at the CNIO and first author of the paper, "the complexity
of human beings does not only result from the number of proteins that
we have, but primarily from how they interact with each other.
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
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
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.
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.