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Nature Communications. Neuronal ‘gateway’ for essential molecules in learning and memory observed at the atomic level

17.04.2024

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María Martínez Molledo, first author of the study, an Óscar Llorca, senior coauthor. She is a researcher and he is the leader at the CNIO's Macromolecular Complexes in DNA Damage Response Group. Credit: Esther Sánchez / CNIO. María Martínez Molledo, first author of the study, an Óscar Llorca, senior coauthor. She is a researcher and he is the leader at the CNIO's Macromolecular Complexes in DNA Damage Response Group. Credit: Esther Sánchez / CNIO.

The Asc-1 protein acts as the gateway for key amino acids involved in cognitive processes to enter and exit neurons. A new study reveals the protein’s structure and mechanism of action.

The study, published in 'Nature Communications', is a collaboration between CNIO, IRB Barcelona, the University of Barcelona and CIBERER..

The findings could be used to design drugs for schizophrenia, stroke and other neurological diseases.

Learning from an experience, remembering an anecdote, changing an attitude… all our behaviours are the result of the exchange of chemical compounds between neurons —the neurotransmitters. Unravelling what exactly happens at the molecular level when neurons talk to each other, at the synapses, is essential for understanding the human brain in general, and for solving mental health problems in particular.

A new study has succeeded in observing and describing the structure of a protein present in the membrane of neurons, a protein that functions like a gate that opens and closes. It acts as a specific transporter for certain amino acids that are key to learning and memory. The protein is called Asc1/CD98hc, or Asc-1 for short.

Structure of the transporter protein Asc1/CD98hc with its two componets: CD98hc (fuchsia) and Asc1 (multicolor), which extend from the inside of the cell (cytoplasm) to the outside, crossing its membrane.
Structure of the transporter protein Asc1/CD98hc with its two componets: CD98hc (fuchsia) and Asc1 (multicolor), which extend from the inside of the cell (cytoplasm) to the outside, crossing its membrane. Insert: EM image where the CD98hc component is shown protruding from the membrane. The Asc1 protein appears as darker parallel stripes on the membrane.

The study, published in Nature Communications, is a collaboration between the Spanish National Cancer Research Centre (CNIO), the Institute for Research in Biomedicine (IRB Barcelona), the Centre for Biomedical Research on Rare Diseases Network (CIBERER) and the University of Barcelona.

The activity of the Asc-1 protein has been linked to different types of mental illness, and understanding its three-dimensional shape will allow the development of new drugs for these pathologies.

Óscar Llorca, leader of the Macromolecular Complexes in DNA Damage Response Group, of the CNIO explains: “Modulating Asc-1 activity could serve as a therapeutic strategy for conditions such as stroke and schizophrenia. Determining the structure of Asc-1 at atomic resolution is important because it can help in the search for compounds that modify its activity”.

“The collaboration between IRB Barcelona and the CNIO has been played a pivotal role in unravelling the mysteries of Asc-1, giving us unprecedented insight into its structure and function. This discovery not only sheds light on the complex cellular machinery underlying fundamental cognitive processes, but also brings us closer to the development of more precise therapeutic interventions for a range of neurological disorders,” adds Manuel Palacín, head of the Amino Acid Transporters and Disease Group at IRB Barcelona.

In addition to Óscar Llorca and Manuel Palacín, Ekaitz Errasti-Murugarren, from the University of Barcelona and CIBERER, is co-author of this work. The first authors are Josep Rullo-Tubau (IRB Barcelona) and María Martínez Molledo (CNIO). Martínez Molledo started at CNIO with a contract funded by the philantropic initiative CNIO Friends.

The work has been funded mainly by the “la Caixa” Foundation and the Ministry of Science, Innovation and Universities.

(From left to right): Manuel Palacín, Josep Rullo-Tubau y Paola Bartoccioni, who has also taken part in the study. All of them at IRB Barcelona. Credit: IRB.

Implications in neurological diseases

All cells in the body have gateways in their membranes for exchanging substances with the outside environment: proteins that constantly open and close according to the needs of the cell. They open inwards to take up an amino acid, for example, and release it by changing shape and opening outwards, or vice versa.

The Asc-1 protein is mainly found in neurons of the hippocampus and cerebral cortex in the brain. It specialises in getting two amino acids into and/or out of the neuron; these amino acids are essential for the neural connections (synapses) involved in learning, memory and brain plasticity —the ability of the nervous system to modify its circuits in response to new environments.

Fluctuations in the supply of these amino acids, called D-serine and glycine, have been linked to schizophrenia, stroke, ALS and other neurological diseases. Efforts have long been underway to develop drugs that regulate Asc-1 activity to treat these diseases, so far without success. A detailed understanding of the atomic structure of Asc-1 provides key information to achieve this goal.

Trapped in the open position to the interior

The Asc-1 protein was purified by Josep Rullo-Tubau at IRB Barcelona and transferred to CNIO, so that María Martínez-Molledo could observe it with cryo-microscopy and use these images to determine the structure of Asc-1 in 3D and high resolution. Electron cryo-microscopy involves freezing molecules at high speed and observing them under an electron microscope, using advanced imaging techniques to interpret the data. 

The observed structure shows Asc-1 at a stage where the gateway is open to the interior of the cell, waiting to receive an amino acid to be transported.

“From its atomic structure, we were able to predict which parts of the protein seem to be important for binding the amino acid to be transported, and the potential mechanism for its transport out of the cell,” says Llorca.

The groups of Víctor Guallar (Barcelona Supercomputing Centre) and Lucía Díaz (Nostrum Biodiscovery) made these predictions about the functioning of the transporter, which were tested by Rullo-Tubau by measuring the effect of specific mutations in Asc-1, supported by Rafael Artuch (Hospital San Joan de Deu) and the Biostatistics and Bioinformatics scientific platform at IRB Barcelona, led by Camille Stephan-Otto Attolini.

Two modus operandi

The findings also help to explain another peculiarity of Asc-1. While the other transporters in its family, called HATs, can only transport one amino acid into the cell if they simultaneously remove another, and vice versa. In other words, they only work by exchanging amino acids. Asc-1, on the other hand, can also remove an amino acid without introducing another one, opening and closing “in vacuo”. This mode of action is known as diffusion.

The results obtained on the molecular structure of Asc-1 provide data for a better understanding of the role of each mode of transport.


Reference article

Referencia del artículo:

Rullo-Tubau, J., Martinez-Molledo, M., Bartoccioni, P. et al. “Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter”. Nat Commun 15, 2986 (2024).

DOI: https://doi.org/10.1038/s41467-024-47385-3

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