The protein ‘MIPS’ alters its internal configuration upon activation. Its previously disorganized active site transforms into a structured form with specific roles. MIPS is essential for synthesizing inositol, also recognized as vitamin B8, which plays crucial roles in bodily functions. For the first time, researchers from Martin Luther University Halle-Wittenberg (MLU) and the National Hellenic Research Centre in Greece have successfully observed this protein restructuring. Their findings are detailed in the scientific journal ‘Proceedings of the National Academy of Sciences’ (PNAS), indicating that this phenomenon may occur in a variety of similar proteins.
Proteins are responsible for regulating all vital functions within living organisms, including growth and metabolism. A fundamental principle in protein science is that a protein’s function is dictated by its structure. If there is a disruption in the structure at even a single point, the protein may be rendered nonfunctional, potentially leading to severe health issues in humans.
Nonetheless, many proteins lack a stable structure, either entirely or in part. These proteins are not only challenging to study but also exhibit structural changes based on their surroundings. “Proteins are typically isolated from their sources before analysis, which does not reveal their behavior in natural conditions. We have developed a method that allows us to investigate proteins under nearly authentic conditions,” clarifies Professor Panagiotis Kastritis, a biochemist at MLU.
The research team focused on samples from the fungus Thermochaetoides thermophila, commonly used in scientific studies. Their primary focus was the protein myo-inositol-1-phosphate synthase (MIPS), crucial for inositol production. Known as vitamin B8, inositol is necessary for various important biological processes but is not deemed a traditional vitamin since the body can synthesize it. “MIPS is part of a lengthy metabolic pathway leading to inositol production,” points out Toni Träger from MLU. Träger, who previously studied this protein for his master’s thesis, is now a member of Kastritis’s research group. By employing cryo-electron microscopy, the scientists observed MIPS functioning and discovered it exists in at least three distinct forms: a disordered form, an ordered form, and a unique intermediate form. “We haven’t definitively determined the purpose of this third state yet. It might assist in water uptake, aiding subsequent processes, or it could serve an entirely different function,” Kastritis notes.
The researchers then explored if proteins similar to MIPS display analogous behaviors. MIPS is categorized as part of a specific class of proteins called isomerases. The team examined structural data on over 340 other isomerases and indeed found strong evidence suggesting similar behaviors in these proteins.
These discoveries hold significance beyond fundamental research. “A deeper understanding of metabolic pathways and the proteins involved could pave the way for new therapeutic options. Our research presents an essential preliminary step,” Kastritis concludes.
This research was supported by funding from the European Union, the Federal Ministry of Education and Research, the German Research Foundation under the Research Training Group GRK 2467, and the European Regional Development Fund.
