The HAT family of proteins are essential for life, because thanks to them amino acids can cross the cell membrane. Although they are almost identical, some carry amino acids and others do not. This specialization is behind the reason why they are involved in specific functions, such as cell growth or the functioning of neurons. And, therefore, they are related to diseases such as cancer or Alzheimer’s. What gives them this specificity and diversity of functions? This is the question that researchers from the National Center for Oncological Research (CNIO) and the Institute for Biomedical Research (IRB Barcelona) who are leading the study we analyze, and whose answer is published this week in the journal Proceedings of the National Academy of Sciences ( PNAS).
For this study, electronic cryomicroscopy and other technologies with high structural resolution have been great allies, as they have the ability to offer images of HAT structures with atomic detail. Combined with a computational model and mutant design of proteins, they have managed to understand how they work a little better. The results of the study 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 going to bind, and are, therefore, responsible for developing one function or another.
Amino acids are the basic building blocks that allow life. They leave and enter cells so that they can carry out activities such as growth, division or the execution of physiological functions. Entry and exit can take place thanks to gates in cell membranes and are made up of HAT family proteins, as well as other molecules. The study researchers set out to unravel the three-dimensional structure of this important family of proteins.
Óscar Llorca is the head of the Group of Macromolecular Complexes in Response to DNA Damage at the CNIO and director of the Center’s Structural Biology Program. He is one of the co-authors of the work and regarding imaging techniques he has commented:
“More traditional techniques for determining the structure of proteins such as those using X-rays have had limited success with proteins that are embedded in biological membranes, so many questions have remained unanswered.”
On the other hand, Manuel Palacín, head of the Amino Acid Transporters and Disease laboratory at IRB Barcelona, also spoke about the new structural imaging techniques used:
“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 to identify the molecular mechanisms that make these proteins transport some amino acids and not others ”.
We are currently living the golden age of three-dimensional structures, especially thanks to electronic cryomicroscopy techniques. The development of this technique won the Nobel Prize in Chemistry in 2017, which went equally to Jacques Dubochet, Joachim Frank and Richard Henderson. The three biophysicists received the award “for developing electronic cryomicroscopy for the high-resolution structural determination of biomolecules in solution.” But knowing the structure in such an intimate way is also helping to accelerate the development of new compounds and drugs of interest in the fight against cancer and other human diseases. With this technique, the researchers of the Spanish team have managed to determine the exact site where the amino acids they transport bind, in addition to the detail in which the recognition of said amino acids takes place. He has discovered the pocket where HAT proteins carry selected amino acids. They have also been able to see that the substitution of some residues for others in specific positions is responsible for the change in the specificity of the recognition and transport of some amino acids or others.
The article titled Structural basis for substrate specificity of heteromeric transporters of neutral amino acids is published this week in Proceedings of the Natural Academy of Science. The eleven authors are members of the CNIO and IRB Barcelona. The work has been carried out in collaboration with the groups of Víctor Guallar, at the Barcelona Supercomputing Center (BSC) and Lucía Díaz from the biotechnology company Nostrum Biodiscovery. The study was made possible thanks to the CaixaResearch program of the “la Caixa” Foundation and funding from the Ministry of Science and Innovation, the Carlos III Health Institute, the Center for Biomedical Research Network on Rare Diseases (CIBERER), the European Fund for Regional Development and the Generalitat de Catalunya.
María A. Blasco, director of the CNIO (National Cancer Research Center), states on the website of said center: “One of our main objectives is to understand why cancer occurs. We are sure that only by fully understanding the reasons for cancer will we learn to avoid it and, if it appears, to detect it and fight it effectively ”. On the other hand, the objective of IRB Barcelona is to carry out research of excellence in biomedicine and improve people’s quality of life and, in parallel, promote the training of talent, technology transfer and the social communication of science. The 27 laboratories and eight technology platforms work to answer basic questions in biology and oriented to diseases such as cancer, metastasis, Alzheimer’s, diabetes and rare diseases. It is an international center that welcomes around 400 workers of more than 30 nationalities.
