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Model of receptor actication IRR
The group of the researchers from Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry together with the student from Moscow Institute of Physics and Technology studied structural features of the receptor IRR (IRR - Insulin receptor-related receptor) and proposed a model of its activation, which has been described in detail in an article published in Biochimie.
This receptor is a tyrosine kinase receptor and belongs to the mini-insulin receptor family, which included insulin receptor (IR) and insulin-like growth factor receptor (IGF-IR). In contrast to other receptor tyrosine kinases IRR is activated by alkaline environment (pH>7.9). In the laboratory of Receptor Cell Biology headed by Dr. Alexander Petrenko first work has been done to determine the specific receptor sites of IRR, responsible for receptor activation in alkaline conditions.
The study of IRR receptor began in 2005 after scientists find a way to activate the receptor, which could not reach the rest. It was found that this receptor is not active in the neutral medium for the growth of cells, which is saturated with 5% carbon dioxide. However, when in contact with the medium normal atmosphere carbon dioxide partially evaporates and the pH changes from neutral to slightly alkaline. In these circumstances, rapid activation of the receptor IRR was seen, prompting scientists suggest a connection between medium pH and activation of the receptor tyrosine kinase. Next, the scientists showed that the other members of the insulin receptor mini-family in such circumstances are not activated, indicating the unique properties of IRR. These data were published in 2011 year at scientific journal Cell Metabolism.
Standard laboratory methods for analyzing the activation of receptor tyrosine kinases are of good quality and therefore not suited for finding the important regions of the molecule IRR, responsible for the pH sensitivity. A senior fellow at the Laboratory of Receptor Cell Biology, Institute of Bioorganic Chemistry, Igor Deyev developed and first used in a series of experiments the new method of receptor activation - autophosphorylation in vitro, which allows you to compare quantitatively the activation of the receptor and its mutants.
Using this method, it was shown that the receptor IRR has two main sites involved in its response to pH changes. The first is located between L1C domains of one monomeric subunit and domains FnIII-2 and FnIII-3 from a second monomer, and the second between L2 and FnIII-1 domains. Wherein the first site has a greater significance for the successful activation of the receptor. Based on experimental data obtained with the laboratory simulation of biomolecular systems under the guidance of Dr. Roman Efremov proposed a model of receptor activation IRR.Also researchers discovered that the receptor IRR has strong "positive" cooperative, that is, for example, activation of the first site of pH-sensitivity results in more light activation of the second pH-site sensitivity. This observation fits well with the proposed model. According to this property, IRR receptor like hemoglobin, which binds in the same way the oxygen molecules in the blood.
Even in 2011, together with the researchers from the Institute of Cytology headed by Academician Nikolsky it had been shown that phosphorylation of IRR triggers intracellular signaling cascade, similar to the cellular response to insulin. Further study of receptor IRR can make a significant contribution to the understanding of the processes occurring both in physiological activation of the insulin receptor and in pathological disorders occurring in patients with diabetes mellitus. Data on the structure and physiological role of receptor IRR could form the basis for the creation of new effective methods for diagnosis and treatment of such patients.
april 14, 2015