Study form the basis of therapeutic strategies to fight against cancers caused by the HMGA1a

Researchers led by Professor Raphael Stoll are therefore waiting for their results to form a basis for future therapeutic strategies to fight cancers caused by HMGA1a. They report in the newspaper Nucleic acid research July 24, 2019.

While the correct function of many proteins depends on their three-dimensional structure, some seem to adopt random forms. For one of them, a team of researchers from the Ruhr-Universität Bochum (RUB) showed that the supposed disorder is not a disorder after all: the HMGA1a protein adopts dynamic structures , more compact, which depend on its phosphorylation. A malfunction of HMGA1a can lead to cancer. Researchers led by Professor Raphael Stoll are therefore waiting for their results to form a basis for future therapeutic strategies to fight cancers caused by HMGA1a. They report in the newspaper Nucleic acid research July 24, 2019.

Many, but not all, proteins in a living cell have a definite three-dimensional structure, which is absolutely necessary for their correct activity. The interrelation between the structure and function of proteins is at the center of many research initiatives that extend to the development of innovative medicines.

At least 30% of all proteins are unstructured

However, on the basis of recent research results, it is expected that at least 30% of all core-containing cell proteins will be partially or even completely unstructured ",

Raphael Stoll, Head, Research Group on Biomolecular Spectroscopy

Despite or precisely because of this remarkable characteristic, these proteins have special, sometimes crucial, functions in healthy and disease-causing processes. These include, for example, the regulation of the cell cycle, the transmission of biological signals and the development of cancers or neurodegenerative diseases such as Alzheimer's or Parkinson's disease.

One of these seemingly disordered proteins is the high mobility A1a group protein (HMGA1a). It is very abundant in the cell nucleus and is important for embryonic development, cell differentiation and also participates in the development of uncontrolled cell proliferation, called neoplasia.

The first complete structural model

The Bochum-based research team was able to demonstrate for the first time that the HMGA1a protein did not adopt completely random forms, but rather dynamic, more compact structures. This allowed the researchers to create the first complete structural model of the HMGA1a protein.

They also described the structural effects of phosphorylation of HMGA1a protein on its function. The binding of phosphoryl groups modifies the function of many proteins and these are therefore activated or deactivated. Phosphoryl groups can also influence the ability of the protein to bind to other cellular components. HMGA1a binds to DNA. This process is very important for its mode of biological action because HMGA1a, for example, participates in the regulation of RNA formation and chromosome rearrangement.

Structure and link probabilities change

The researchers applied nuclear magnetic resonance spectroscopy, able to provide information not only on the structure, but also on the dynamics of proteins. "Our results show that the dynamic and compact structures of this protein depend on its phosphorylation state," reports Raphael Stoll. Within the cell, the protein HMGA1a is phosphorylated by casein kinase 2. This has an effect on the electrostatic network of the protein HMGA1a and thus modifies the dynamic structural badembly of this protein. Other experiments revealed that these changes even affected the ability of the HMGA1a protein to bind to its natural target sequence in the DNA of the cell nucleus.