Recent research reveals that, during the development of different tumor processes, there is a relationship between two proteins that, in principle, should not be associated for any specific function in the body.
The study was carried out by a team of scientists from the University of Granada, the Miguel Hernández University of Elche, the University of Zaragoza and the Foundation for the Promotion of Health and Biomedical Research of the Valencian Community (FISABIO).
Through computational analysis and in vitro tests, the work shows for the first time how these proteins interact, and opens new avenues to understand how lung cancer, among others, develops.
Experts already knew the characteristics of these proteins, called PADI4 and PKP1, separately. They described their properties, the places where they are found, and their interactions with other molecules. Both appear in tumor processes and are related to other macromolecules with similar characteristics, which is why they decided to unite them to analyze their affinity. The authors of the new study show how this relationship is established and what role both play in the proliferation of cancer cells. The research opens new avenues to find out the real scope of this type of union in the development of diseases and to be able to better combat them.
PADI4 is normally found in the cell nucleus where it binds to other proteins known as ARMs (with armadillo repeat domains). This protein structure is what allows its passage to the heart of the cell. ARM-PKP1 has these domains. “The interest of the research lies in describing the ARM-PKP interactome and analyzing in vitro the affinity of their relationships. In other words, it is as if we deployed the social networks of the proteins in the cell to find out everything about them”, the researcher at the University of Granada Esther Fárez Vidal, co-author of the study, told the Discover Foundation.
In previous work, the group showed that PADI4 alters the functions of p53, a cancer suppressor gene, promoting the proliferation of various tumors. It also modifies some of the amino acids in other proteins, changing their structure through a process called citrullination.
Furthermore, they related ARM-PKP1 to MYC, a known tumor-promoting gene, and proposed ARM-PKP1 as a marker for the diagnosis of lung cancer. Likewise, they demonstrated that it forms part of the desmosomes, which are the points of union of the cells with each other with which the tissues are created. It could be said that they are the thread with which the organism is sewn. For its part, PADI4 can add buttons of one color or another to that suit through citrullination.
With the biochemical study of all the proteins and nucleic acids involved in the development of different types of cancer, it is possible to understand the changes that occur in the development of tumors at the molecular level. These modifications affect the function they perform when the cell is healthy.
On the other hand, biophysics allows us to know how these chemical components are ordered, how they interact with each other in each cell compartment or under a specific circumstance and describes the action they perform. In the same way that ice has different properties than water vapor, the biophysics of proteins determines how they act and with whom they interact according to the conditions of their environment. “Our findings allow us to deepen our knowledge of the development of tumors in which these two proteins are involved”, indicates the researcher from the Miguel Hernández José Luis Neira University.
In addition to establishing for the first time the relationship between the two proteins in the development of some tumors, the work opens the way to understanding the function and describing the formation of a defense mechanism against pathogens called neutrophil extracellular traps (NETs). These are formed by networks of protein fibers and nucleic acids from neutrophils, the cells that act as the first defense against infection. The NETs work as if it were a strainer, creating a mesh that sifts and entangles viruses or bacteria.
Its construction is modulated by PADI4, so the experts thought that ARM-PKP1 could also intervene in them. Thus, the discovery of the relationship between PADI4 and ARM-PKP1 may help to understand how the immune system works. “These studies suggest that PADI4 could regulate the function of ARM-PKP1, hindering interactions with other proteins, which is of great importance in various diseases, including cancer,” says FISABIO researcher Camino de Juan.
The work shows for the first time how PADI4 and ARM-PKP1 interact, through computational studies and in vitro assays. (Image: Discover Foundation)
Experts continue their research in this field with the aim of finding treatments that prevent the development of a specific type of tumor or alter the formation of NETs. “If it is confirmed that the union of both proteins favors the development of tumors, as the results of this study seem to suggest, it could be prevented by developing drugs that adhere to at least one of them at the same point that they use to interact. ”, the experts conclude.
The study is titled “The armadillo-repeat domain of Plakophilin 1 binds to human enzyme PADI4”. And it has been published in the academic journal Biochimica et Biophysica Acta – Proteins and Proteomics. (Source: Discover Foundation)