HAT amino acid transporters are involved in pathologies such as aminoacidurias, cancer, viral infections and cocaine addiction.
The breakthrough published in the Proceedings of the National Academy of Science USA allows researchers to delve into the functions of HATs and to address the rational drug design of inhibitors.
The study has been partially funded by the European project EDICT (European Drug Initiative on Channels and Transporters), devoted to increasing the number of membrane protein structures available.
The researcher Manuel Palacín, head of the Heterogenic and Multigenic Diseases lab at the Institute for Research in Biomedicine (IRB), in Barcelona, is among the world’s experts in HATs (heteromeric amino acid transporters).
In humans, there are eight HAT molecules. These are associated, for example, with the following: rare diseases called aminoacidurias, such as lysinuric protein intolerance and cystinuria; the development of infections caused by the Kaposi sarcoma virus; various types of cancer; and relapse in cocaine use. HATs are, as the name implies, amino acid transporters, and they exert their action in the cell membrane. Because of their nature, they are extremely difficult to crystallize and consequently no structural data are available for these molecules at the atomic level. However, for rational drug design this information is imperative.
A study published this week in the journal Proceedings of the National Academy of Sciences USA (PNAS) has revealed the first structure of one of the eight HATs. Achieved through collaboration between biochemists at IRB, experts in electronic microscopy at the University of Bern, and computational biologists in the Joint IRB-BSC Programme, this breakthrough paves the way for further research into the functions of the other seven HATs and the resolution of their structures. Moreover, this study provides the first sufficiently detailed structural data to tackle their inhibition through drugs.
HATs and human pathologies
HAT proteins are formed by two parts or subunits, a light one which serves to transport amino acids and a heavier one that allows movement of the complex to the cell membrane, conferring it stability. In humans, six transporters form a complex with 4F2hc, while two do so with rBAT, thus totalling eight HATs. “They are mini machines that are inserted into the membrane and are in constant movement, engulfing amino acids from the extracellular space and releasing them in the cytoplasm or vice-versa,” explains Palacín. “We knew the structure of one of the parts. Now, for the first time, we have the low resolution of the entire complex,” he says.
The study, whose first four authors include the post-doctoral researcher Albert Rosell and the PhD student Elena Álvarez-Marimon at IRB Barcelona, describes the structure of the 4F2hc/LAT2 complex. “We chose this complex because it shows the highest stability among human HATs and would allow a greater chance of tackling its structure. The next step is to move onto its atomic resolution,” explains Rosell. “Resolution at this level, at the highest definition, will help us to study the details of how “the machine” works and to gain a greater knowledge regarding the precise drug targets,” add the scientists.
Only some HATs are associated with diseases. The 4F2hc/LAT1 and 4F2hc/xCT complexes are overexpressed in many kinds of cancer. “We have better and more detailed knowledge about the complexes and so we are providing new options by which to deal with cancer,” says Manuel Palacín. The lab also focuses on aminoacidurias. Mutation in the 4F2hc/y+LAT1 complex causes lysinuric protein intolerance, a rare disease with 200 known cases. Finally, mutations in the rBAT/b(0,+)AT complex lead to cystinuria, a condition with an estimated incidence of one case per 7,000 births.
Manuel Palacín’s basic research into HATs seeks to identify new therapeutic targets and to improve diagnostic tools for all conditions that involve HATs, with a special focus on aminoacidurias.
The study started as part of the European project EDICT (European Drug Initiative on Channels and Transporters), a consortium comprising 21 groups and funded by 11 million euros, which aims to increase the database of membrane protein structures. In 2008, at the beginning of the project, about 100 membrane protein structures were known. Today, this number has tripled, Palacín’s group having contributed two of these new structures.Reference article:
Proceedings of the National Academy of Sciences USA (PNAS) Early Edition 10 February 2014, doi:10.1038/nbt.2831
Sònia Armengou | EurekAlert!
Drone vs. truck deliveries: Which create less carbon pollution?
31.05.2017 | University of Washington
New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
23.06.2017 | Physics and Astronomy
23.06.2017 | Physics and Astronomy
23.06.2017 | Information Technology