Identified the mechanism of action of the C1GalT1 protein, an enzyme with great involvement in the development and progression of cancer

The magazine Nature Communications. publishes the identification of the mechanism of action of the C1GalT1 protein and its involvement in cancer, a discovery that has been achieved by a scientific team from the University of Zaragoza, through the use of biochemical, biophysical and computational techniques.

 

Specifically, the research group of Ramón Hurtado-Guerrero, ARAID researcher at the Institute of Biocomputing and Physics of Complex Systems (BIFI-Unify), has managed to obtain the three-dimensional structure and mechanism of action of this protein, whose malfunction is related to a increased aggressiveness and metastasis of at least 90% of human cancers.

 

The proteins They are important molecules for the cells that make up Our organism perform all functions necessary biological and physiological functions correctly. The vast majority of these proteins necesitan that certain of his amino acids (preferably in our case serine and threonine residues) are modified by joining them to sugars to preserve its structure and perform its function correctly. 

 

For the vast majority of proteins to carry out their function, They must go through a process called 'glycosylation', which consists of They are modified by binding to sugars.

 

La glycosylation It is a process that takes place in several stages although the first two stages are decisive and are closely related to cancer. In First intervene N-acetylgalactosaminyl transferases (GalNAc-Ts). There is more of 20 different types of these proteins, of great interest to researchers because their malfunction can lead to diseases such as cancer or osteoporosis.

 

En second place interviene the enzyme C1GalT1, that It is key to a process called elongation and that is central in the formation of the O-glycans. After elongation, other enzymes carry out their functions forming what are called O-complex glycans. In most of tumors, this protein does not work correctly, which causes poorly glycosylated proteins to accumulate, called Tn antigen. Tn antigens promote tumor metastasis, so the malfunction of C1GalT1 leads to more aggressive tumors. Knowing its structure and mechanism of action could help develop strategies to regulate its operation.

 

The predoctoral researcher Andrés Manuel González-Ramírez, under the supervision of Dr. Ramón Hurtado-Guerrero, ARAID researcher at the Institute of Biocomputing and Physics of Complex Systems (BIFI) in Zaragoza and visiting researcher at the University of Copenhagen, in collaboration with different national and international groups (Francisco Corzana de la University of La Rioja, Henrik Clausen of the University of Copenhagen and Filipa Marcelo de la NOVA University of Lisbon), they have revealed through the use of biochemical, biophysical, cellular and computational techniques the three-dimensional structure and mode of action of C1GalT1.

 

Specifically, in a study published on May 3 in the magazine Nature Communications., these researchers have shown, thanks to obtaining the three-dimensional structure of fly C1GalT1, which C1GalT1 is capable of forcing the glycosylated threonine to adopt a shape similar to that of glycosylated serine amino acids in nature, which allows it to perform its function correctly on both types of substrate indiscriminately following the typical mechanism of the family of glycosyltransferases. the one that belongs. Furthermore, it has been revealed that for For this to function correctly, two units of C1GalT1 must be linked (also called a dimer for simplicity).. Finally, they have managed to reveal that the binding to its two substrates is mainly due to the fact that this enzyme recognizes the sugar group, although other factors such as the peptide sequence can help this binding occur more efficiently.

 

Definitely, "These studies help us better understand an enzyme that intervenes in a ground process biologically, such as protein glycosylation and whose malfunction can cause effects as serious as the proliferation of cancer and metastasis”, they highlight the researchers Ramón Hurtado-Guerrero and Andrés Manuel González-Ramírez.

 

“It is incredibly curious that C1GalT1 can carry out its biological function so precisely on different substrates with this peculiar strategy of forcing one substrate to resemble the other,” they add. “We could also hypothesize that in cases of cancer in which C1GalT1 does not function correctly, it is due to the fact that the biological dimer of this enzyme has not been able to form. "These discoveries help us to better understand the functioning of glycosyltransferases in general to eventually be able to understand, as a whole, the complex process of glycosylation."