They observe the neural gate for molecules essential in learning and memory

Scientists have observed at the atomic level the neuronal “gate” for molecules that are essential in learning and memory.

Learning from an experience, remembering an anecdote, modifying an attitude… All our behavior is the result of the exchange of chemical compounds between neurons – neurotransmitters. Unraveling what exactly happens on a molecular scale when neurons talk to each other, in synapses, is essential to understanding the human brain in general, and in particular to contribute to solving mental health problems.

A new study, published in the academic journal Nature Communications, has managed to observe and describe the structure of a protein present in the membrane of neurons, a protein that acts like a gate that opens and closes. It acts as a specific transporter for certain key amino acids for learning and memory. This is the protein Asc1/CD98hc (Asc1 in its abbreviated form).

The work is a collaboration of the National Cancer Research Center (CNIO), the Barcelona Biomedical Research Institute (IRB Barcelona), the University of Barcelona (UB) and the Networked Biomedical Research Center for Rare Diseases (CIBERER), in Spain.

The activity of the Asc1 protein has been related to different types of mental illness, and knowing its three-dimensional shape will allow the development of new drugs for these pathologies.

Dr. Óscar Llorca, from the CNIO, explains it: “Modulating the activity of Asc1 can be a therapeutic strategy in conditions such as stroke and schizophrenia. “Determining the structure of Asc1 at atomic resolution is important because it can help in the search for compounds that modify its activity.”

“The collaboration between IRB Barcelona, ​​the CNIO and the UB has been key to unraveling the mysteries of Asc1, offering us an unprecedented vision of its structure and functioning. “This discovery not only sheds light on the complex cellular machinery underlying fundamental cognitive processes, but also brings us closer to developing more precise therapeutic interventions for a range of neurological disorders,” adds Dr. Manuel Palacín, head of the Transporters Laboratory. Amino acids and Diseases at IRB Barcelona and professor at the Department of Biochemistry and Molecular Biomedicine of the Faculty of Biology of the UB.

In addition to Dr. Óscar Llorca and Dr. Manuel Palacín, Dr. Ekaitz Errasti-Murugarren, from the University of Barcelona and CIBERER, is co-author of this work. The first signatories are Josep Rullo-Tubau (IRB Barcelona) and Dr. María Martínez Molledo (CNIO).

Implication in neurological diseases

All cells in the body have gates in their membrane to exchange substances with the outside environment: proteins that are continually opening and closing according to the needs of the cell. They open inwards, they take, for example, an amino acid and, with a modification in its shape, they release it by opening towards the outside, or vice versa.

The Asc1 protein is mainly in the neurons of the hippocampus and cerebral cortex, in the brain. It specializes in introducing and/or removing from the neuron two essential amino acids for neuronal 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 associated with schizophrenia, stroke, ALS and other neurological diseases. Attempts have been made for some time to design drugs that regulate the activity of Asc1 to treat these diseases, but without success. Knowing the atomic structure of Asc1 in detail provides key information to achieve this.

Intercepted when opening inwards

The Asc1 protein was purified by Josep Rullo-Tubau at IRB Barcelona, ​​and transferred to the CNIO so that Dr. María Martínez-Molledo could observe them with cryo-electron microscopy and with these images she could determine the structure of Asc1 in 3D and high resolution. In cryo-electron microscopy, molecules are frozen at high speed and observed in electron microscopes; Advanced imaging techniques are then used to interpret the information.

The observed structure shows Asc1 when it has been trapped in a stage in which the gate was open towards 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 that is going to be transported, and the possible mechanism for its transport to the outside of the cell,” says Dr. Llorca.

The groups of Dr. Víctor Guallar (Barcelona Supercomputing Center) and Dr. Lucía Díaz (Nostrum Biodiscovery) made these predictions about the functioning of the transporter, which were tested by Josep Rullo-Tubau, by measuring the effect of specific mutations in Asc1, which were complemented by Dr. Rafael Artuch (San Joan de Déu Hospital) and the scientific platform of Biostatistics and Bioinformatics of IRB Barcelona, ​​led by Dr. Camille Stephan-Otto Attolini.

Structure of the transporter protein Asc1/CD98hc with its two components: CD98hc (fuchsia) and Asc1 (multicolor), which extend from the inside of the cell (cytoplasm) to the outside, crossing its membrane. (Image: CNIO. CC BY-NC-ND)

Two modus operandi

The conclusions also contribute to explaining another peculiarity of Asc1. A The rest of the family of transporters to which it belongs, called HAT, can only transport one amino acid into the cell when they take another out, and vice versa. That is, they function only by exchanging amino acids. Asc1, however, can also extract an amino acid without the need to introduce another and open and close “in a vacuum”. This mode of activity is called “diffusion.”

The results obtained on the molecular structure of Asc1 provide data to better understand the function of each of the transport modes. (Source: IRB Barcelona)