While the correct function of many proteins depends on their three-dimensional structure, some random shapes seem to be assumed. For one of them, a research team from the Ruhr-Universität Bochum (RUB) has shown that the putative disorder is nonexistent: The protein HMGA1a assumes dynamic, more compact structures that depend on its phosphorylation. Malfunction of HMGA1a can lead to cancer. The researchers around Prof. Dr. Raphael Stoll therefore expect their results to be a basis for future therapeutic strategies against cancers caused by HMGA1a. They report in the journal Nucleic Acids Research of 24 July 2019.
Many – but not all – proteins in a living cell have a defined three-dimensional structure that is absolutely necessary for their proper activity. The mutual relationship between structure and function of proteins is the focus of many research initiatives that extend to the development of novel drugs.
At least 30 percent of all proteins are unstructured
“However, based on recent research, it is predicted that at least 30 percent of all proteins in nucleated cells are partially or even completely unstructured,” said Raphael Stoll, head of the Biomolecular Spectroscopy Group. Despite or because of this peculiarity, these proteins have special, sometimes crucial functions in both healthy and pathogenic processes. These include, for example, the regulation of the cell cycle, the transmission of biological signals, but also the development of cancer or neurodegenerative diseases such as Alzheimer’s or Parkinson’s.
One of these seemingly disordered proteins is the High Mobility Group Protein A1a (HMGA1a). It is present in large numbers in the cell nucleus and is important for embryonic development, cell differentiation, but also involved in the development of uncontrolled cell proliferation, so-called neoplasias.
The first full-length structural model
For the first time, the Bochum research team has been able to show that the HMGA1a protein does not assume random shapes but dynamic, more compact structures. This allowed the scientists to create the first structural model of the HMGA1a protein in full length.
In addition, they were able to show the structural effects of the phosphorylation of the HMGA1a protein on the natural protein function. By attaching phosphoryl groups, many proteins are changed in their function and thus switched on or off. In addition, phosphoryl groups can affect the ability of the protein to bind to other cell components. HMGA1a binds to the DNA. This process is very important for its biological mode of action, for example, because HMGA1a is involved in regulating the formation of RNA and reorganizing the chromosomes.
Structure and bonding possibilities change
The researchers used nuclear magnetic resonance spectroscopy, which can provide not only information 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. In the cell, the HMGA1a protein is phosphorylated by the so-called casein kinase 2. This affects the electrostatic network in the HMGA1a protein and thereby alters the dynamic structure ensemble of this protein. Further studies have shown that these changes even affect the ability of the HMGA1a protein to bind to its natural target sequence in the DNA of the nucleus.