2023-08-28 11:15:26
Some scientists have taken another step in the investigation of the process of formation of this hormone from its initial stages to the end. The results of the new study will help to better understand the insulin-related mechanisms that fail in the development of diabetes and other diseases.
“Like all new knowledge in basic science, knowing more about how biological mechanisms work also helps to understand what happens when they go wrong and, in the case of diseases, provides the necessary information to think about different therapeutic strategies”, explains Pamela Toledo. , fellow of the National Scientific and Technical Research Council (CONICET) of Argentina, in the Group of Structural Biology and Biotechnology of the National University of Quilmes (GBEyB, UNQ) linked to the Multidisciplinary Institute of Cellular Biology (IMBICE, CONICET-UNLP-CICPBA ), and co-author of the aforementioned new study, which explores the forms of organization of insulin molecules.
The work, carried out in collaboration with a team from the Technical University of Dresden, Germany, focuses on what happens before insulin reaches the secretory granules, that is, the clusters in which it is concentrated inside the pancreas when it is ready to go into the bloodstream against the entry of sugars that will help convert into energy. “This last stage is widely reported, especially in studies on diabetes, but what is not so well known is how it reaches this maturity, and that is where our work focuses,” says Diego Vazquez, CONICET researcher at the GBEyB and also study co-author.
To analyze these previous stages, the team used proinsulin, a precursor molecule that, after a series of steps and chemical reactions, gives rise to insulin. “In order to experiment with it in the laboratory, we needed to have it in large quantities because it was our raw material. The problem is that commercially there is not so much availability, and it also has a very high cost”, report the specialists. To overcome this difficulty, they developed a production technique that allowed them to obtain their own proinsulin by adapting some known protocols, optimizing its quality and reaching the necessary proportions to carry out the work.
“This was one of the achievements of the research: the own production of human proinsulin as a raw material for biotechnological trials”, says Toledo. And it is that the procedure is not simple at all: it is a protein whose structure has a kind of anchor in different parts, which is very specific to its function. “In addition to achieving its expression, we had to purify it and form this characteristic anchoring pattern of its folding which, if not achieved correctly, results in another protein that is of no use to us,” adds the expert. In this way, the research also reports as a novelty the manufacture of this molecule in the laboratory, which could probably be used to obtain insulin.
From left to right: Diego Vazquez, Pamela Toledo, Mario Ermácora and Milagros Abate, from the research team. (Photo: News Agency of the National University of Quilmes)
Once they managed to manufacture the precursor, they began to study the formation of biomolecular condensates, a mechanism for organizing proteins within cells discovered in the last 20 years. “It is a phenomenon that begins with a separation of ‘liquid-liquid’ phases that we can imagine as a drop of a liquid inside another liquid, with the particularity that they do not mix but they do not remain completely separated either,” explains Vazquez. , and continues: “What we verified is that proinsulin is capable of ordering itself into these clusters on its own, without being forced to do so by any other force or component of the cell. But, in addition, we saw that it forms them in different sizes depending on the pH, which decreases during the process”.
On this point, specialists describe that, in the early stages, when the pH is rather neutral, proinsulin is grouped into large and small condensates, depending on the number of molecules that come together in each drop. Later, as the final conditions are approached, the pH becomes more acidic, that is, becoming acidic, and in this way all the populations of proinsulin come together as one and remain homogenized in a large condensate. The hypothesis postulated by the authors of the research is that this formation of biomolecular condensates would be the mechanism responsible for keeping proinsulin inside the secretion granules and letting it out only once it has been transformed into mature insulin, a phase about which so far little is known.
The study is titled “Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain”. And it has been published in the academic journal Protein Science. (Source: CONICET. CC BY 2.5 AR)
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