Researching in biology (I): The proteasome and the biology of cancer

Biologists study a great diversity of fields of study, one of them and where they perform an important function is in the study of cancer biology, among other examples.

This is the case of Juliana Amodio Debenjak, an Argentine biologist who did her doctorate in the group of structural biology of protein and nucleic acid complexes, belonging to the institutes of Molecular Biology (IBMB-CSIC) and of Biomedical Research of Barcelona (IRB Barcelona) , located in the Parc Cientific de Barcelona .

During his PhD, the main subject of study was a complex of 9 different proteins, called the lid of the regulatory particle of the proteasome. The regulatory particle of the proteasome is 19S and is made up of the lid and the base.

What is the proteasome?

Researching in biology (I): The proteasome and the biology of cancer
Researching in biology (I): The proteasome and the biology of cancer

The proteasome is a complex of many proteins that has a barrel shape and that is responsible for breaking or degrading cellular proteins as necessary, that is, it is like the molecular shredder / dustbin of cells .

For example, it is responsible for degrading misfolded proteins (that is, they do not have the correct structure) due to heat shock, such as infections. It also degrades oxidation-damaged proteins that can form amorphous masses within the cell. A malfunction of the proteasome is thought to be the cause of the accumulation of faulty proteins in nerve cells that leads to Parkinson’s or Alzheimer’s disease.

Moreover, it also plays an important role in the adaptive immune response. It is responsible for degrading the proteins of invading pathogens, and the degradation products generated by the proteasome are antigenic peptides that are expressed in the cell membrane. 

What enters the proteasome to be degraded is regulated by the regulatory particle, and specifically the lid, a complex of 9 proteins that are part of the entrance gate to the proteasome.

Why study the proteasome?

In many types of cancer the proteasome is overexpressed, that is, there are a large number of them working at full speed because the tumor has a high protein metabolism. 

When the structure is known at the atomic level, compounds (drugs) can be designed to inhibit it and develop new cancer drugs.

What techniques are used to study it?

There are different ways to study it, in Juliana’s case she used the crystallography technique . To do this, it is necessary to generate the protein or complex of interest in large quantities, crystallize it and irradiate it with X-rays to obtain diffraction and thus (through mathematical calculations) obtain the structure, that is, how it “looks” in 3D and at the atomic level. .

The first step is to obtain the protein (s) in large quantities. To do this, they are cloned and expressed in bacteria. Using the PCR technique, copies of the gene that are introduced into bacteria are made to synthesize the protein to be studied. When they are cloned (which is what this technique is called) a molecular marker is added, a kind of chemical decoy allows me to purify the protein from the entire bacterial mixture. 

Once all the pure protein is obtained, it is placed under different chemical conditions to crystallize. In a crystal, the particles unite, arranging themselves in an orderly fashion, that order and repetition within the crystal is what allows that when irradiating it with X-rays it is possible to “see” the shape that something so small takes in space. 

From theory to practice: difficulties in study

Knowledge in science is built little by little, as Juliana says “Science is a little ant’s work, where each one contributes his grain of sand and collaboratively we are solving the mysteries that life has in store for us”. 

In the results of her project, Juliana managed to generate complexes of up to 5 proteins that did not crystallize. The reason was found out after another group studied this same complex by electron microscopy: its structure has a glove-like shape where the part similar to the fingers moves a lot, preventing a crystal from being produced. 

Although he could not see the crystallized structure, his work provided information on which parts of the proteins are involved in holding this complex together and that is very important for the development of treatments and drugs focused on the inhibition of this complex.

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