The Mode of Action of Basic Proteins Involved in Cancer and Alzheimer's Disease

Posted by Jerry Carter on December 14th, 2021

These proteins belonging to the HAT family are essential for life because they transport amino acids at the cell membrane. Although members of the family are nearly identical, they selectively transport certain amino acids.

This specificity determines their involvement in specific functions, such as cell growth or neuronal function, and consequently in related diseases, such as cancer or neurodegenerative diseases, such as Alzheimer\'s disease. What confers specificity and diversity to this function? One of the questions asked by researchers at the Spanish National Cancer Research Center (CNIO) and the Biomedical Research Institute (IRB Barcelona), who led the study, whose answers were published in the Proceedings of the National Academy of Sciences (PNAS).

Thanks to recent high-resolution structural techniques such as cryo-electron microscopy, combined with computational modeling and the design of these protein mutants, researchers have been able to observe the structure of a member of this protein family in atomic detail and decipher its function. The results suggest that in this protein family, only a few residues located in specific regions select the specific amino acids they will bind to, thus being responsible for the protein\'s involvement in specific physiological functions.

How to disrupt their function

Amino acids are essential components of life, and they enter and exit cells, allowing cells to grow, divide, and develop their functions. This movement into and out of the cell is due to the gates embedded in the cell membrane, which are composed of proteins of the HAT family, among others.

Although HAT proteins are almost structurally identical, some proteins transport certain amino acids rather than others, thus conferring specific functions to each member of the family, such as involvement in cell growth; role in diseases such as cancer; neurological function; and transport of toxic substances and involvement in addiction to substances such as cocaine.

To understand the specificity of this function, scientists have begun to study the three-dimensional structure of important protein families. “Classical techniques for determining protein structure, such as the use of x-rays, have had limited success for proteins embedded in biofilms, and there are still many unsolved problems.” Oscar Llorca, leader of the macromolecular complex group of the CNIO DNA damage response group, director of the structural biology program at the center, and co-author of the study, said.

“The combination of the structural resolution of cryo-electron microscopy with molecular dynamics calculations and functional studies provides an experimental platform with great potential that allows us to unravel the function of amino acid transporters. In this case, we used this technique to identify the molecular mechanisms that lead these proteins to transport some amino acids rather than others,” Manuel Palacin said.

New drugs for cancer and Alzheimer\'s disease

Due to the advent of cryo-electron microscopy technology, the visualization of protein molecular structures is a major step toward the golden age of 3D structures that we now know. This new technology won the Nobel Prize in Chemistry in 2017, which is not only unprecedented for observing biological processes, but also helps accelerate the development of new compounds and drugs to treat cancer and other human diseases.

In this work, using cryo-electron microscopy, researchers have been able to visualize the structure of HAT family members at atomic resolution and determine the pocket in which these proteins bind to amino acids, and the details of the mechanism by which this recognition occurs.

Atomic details show that only a few residues in these proteins determine the amino acids to which they bind as well as their specific function. In addition, the study demonstrates how substitution of certain residues for others alters recognition and transport specificity of certain amino acids at these positions in different family members.

The results of this study will lead to efforts to study compounds that can act on specific regions of these proteins and manage the diseases in which they are involved, such as cancer and neurodegenerative diseases.