Spanish scientists ‘put a face’ on proteins essential for cell life implicated in cancer or Alzheimer’s

MADRID, 29 Nov. (EUROPA PRESS) –

Researchers from the National Center for Oncological Research (CNIO) and the Institute for Biomedical Research (IRB Barcelona) ‘put face’ on proteins essential for cell life that are implicated in cancer or Alzheimer’s. Specifically, they have revealed the functioning of HAT proteins, which serve as gates for the entry and exit of amino acids into cells.

The HAT family proteins are essential for life – they transport amino acids across the cell membrane. However, being its members practically identical, some carry some amino acids and others do not. This specialization is responsible for each of them being involved in specific functions such as, for example, cell growth or the functioning of neurons, and therefore in related diseases such as cancer or neurodegenerative diseases such as Alzheimer’s.

Thanks to the latest high-resolution structural technologies such as electron cryomicroscopy, researchers have been able to visualize the structure of one of the members of this protein family in atomic detail and, combined with computational modeling and the design of protein mutants , thus understand its operation.

The results of the study, published this week in the journal ‘Proceedings of the National Academy of Sciences’ (PNAS), show that only a few residues of this family of proteins, located in very specific regions, select the specific amino acids to which they are They are going to unite, and are therefore responsible for developing one function or another.

With this information, the great challenge for researchers now is to find new therapies and diagnostic tools for pathologies in which the transporters of the HAT family are involved, with special interest in those diseases that represent serious public health problems such as cancer or neurodegenerative diseases such as Alzheimer’s.

Amino acids, the basic building blocks that allow life, enter and leave cells so that they can grow, divide and carry out their physiological functions. This entry and exit of the cells happens thanks to the gates formed by, among others, the proteins of the HAT family, which are embedded in the cell membranes.

Despite the fact that HAT proteins are practically identical in structure, some carry some amino acids and not others, which gives them completely different functions, such as those related to cell growth and their involvement in diseases such as cancer; the functioning of neurons; or the transport of toxic substances and its implication in addiction to substances such as cocaine.

In order to understand this specificity in function, the scientists set out to study the three-dimensional structure of this important family of proteins. “The more traditional techniques for determining the structure of proteins such as those that use X-rays have had limited success with proteins that are embedded in biological membranes, so many questions have remained unsolved”, says Óscar Llorca, chief of the Group of Macromolecular Complexes in the Response to DNA Damage of the CNIO, director of the Structural Biology Program of the Center and co-author of the work.

“The combination of the resolution of the structure by electron cryo-microscopy with calculations of molecular dynamics and functional studies, represents an experimental platform with great potential that allows us to unravel the functioning of amino acid transporters. In this case, we have applied this technology for the identification of the molecular mechanisms that make these proteins transport some amino acids and not others “, says Manuel Palacín, head of the Amino Acid Transporters and Disease laboratory at IRB Barcelona, ​​group leader at the CIBER for Rare Diseases, and Professor at the University from Barcelona.

NEW DRUGS AGAINST CANCER OR ALZHEIMER

Thanks to the techniques of cryo-electron microscopy, a field in which Llorca is an expert worldwide, the visualization of the molecular structure of proteins has taken a giant step towards what we know today as the golden age of three-dimensional structures. This new technology, which won the Nobel Prize in Chemistry in 2017, has not only served to visualize biological processes like never before, but is also helping to accelerate the development of new compounds and drugs of interest in the fight against cancer and other human diseases.

In this work, the researchers have been able to visualize with atomic resolution, by using cryo-electron microscopy, the structure of a member of the HAT family -the * LAT2 / CD98hc- protein, and to determine the pocket where the amino acids bind. that they transport, as well as the detail of the mechanism by which this recognition occurs.

The atomic detail reveals that only a few residues of these proteins are responsible for dictating the amino acids to which they bind and therefore their specific functions. Furthermore, the work shows how the substitutions of some residues for others in these positions in the different members of the family are responsible for the change in the specificity of recognition and transport of some amino acids and not others.

The results of this research will now make it possible to direct efforts to obtain new drugs that act specifically on specific regions of these proteins, and to control the diseases in which they intervene, such as cancer or neurodegenerative diseases such as Alzheimer’s.

The work, led by IRB Barcelona and the CNIO, has been carried out in collaboration with the groups of Víctor Guallar, at the Barcelona Supercomputing Center (BSC) and Lucía Díaz of the biotechnology company Nostrum Biodiscovery.