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A. G. Petrenko - One of the best experts on this subject based on the ideXlab platform.
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mapping of alkali sensing sites of the Insulin Receptor related Receptor the role of l2 and fibronectin domains
Biochimie, 2015Co-Authors: Igor E Deyev, N. A. Chachina, D. M. Shayahmetova, O. V. Serova, A. G. PetrenkoAbstract:Insulin Receptor-Related Receptor (IRR) is a member of the Insulin Receptor (IR) family that works as an extracellular alkali sensor with positive cooperativity. The pH sensing property of IRR is defined by its extracellular region and involves multiple domains. We have previously demonstrated the primary role of L1C domains and identified potentially important amino acid residues within these domains. In this study, we addressed the roles of L2 and FnIII domains. Within the L2 domain, five amino acid residues (M406, V407, D408, P436 and V437) were identified as IRR-specific by performing a species conservation analysis of the IR family. Single-point mutations of these five residues to alanine produced either little or no negative effect on IRR pH-sensing activity. However, the triple mutation of M406, V407 and D408 (MVD) showed a strong negative effect, with a 4 fold decrease in IRR activity as estimated by in vitro autophosphorylation assay of solubilized Receptors. The analysis of this mutant in intact cells revealed the absence of positive cooperativity. Unexpectedly, the double mutation of vicinal P436 and V437 (PV) exhibited a significant positive effect in the in vitro assay and partial positive cooperativity in the whole-cell assay. The role of FnIII domains was addressed by analyzing chimeras of IRR and IR. When the IRR FnIII domains were swapped with those of IR in different combinations, the activity was significantly reduced and positive cooperativity eliminated. However, two mutants with the targeted C-terminal part of IRR alpha subunit that lies within FnIII-2 domain and have been shown to be important for Insulin binding by IR, appeared to be as active as wild-type IRR. On the basis of available data, we propose that IRR activation involves two separate centers of pH-dependent rearrangements that act synergistically to induce a major conformational change in the IRR molecule, resulting in internal kinase domains rapprochement and autophosphorylation.
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Structural determinants of the Insulin Receptor-Related Receptor activation by alkali
The Journal of biological chemistry, 2013Co-Authors: Igor E Deyev, O. V. Serova, Nadezhda V. Popova, Anastasiya A. Berchatova, Egor S. Zhevlenev, Alla V. Mitrofanova, Nikita Radionov, A. G. PetrenkoAbstract:Abstract IRR is a member of the Insulin Receptor (IR) family that does not have any known agonist of a peptide nature but can be activated by mildly alkaline medium and was thus proposed to function as an extracellular pH sensor. IRR activation by alkali is defined by its N-terminal extracellular region. To reveal key structural elements involved in alkali sensing, we developed an in vitro method to quantify activity of IRR and its mutants. Replacing the IRR L1C domains (residues 1–333) or L2 domain (residues 334–462) or both with the homologous fragments of IR reduced the Receptor activity to 35, 64, and 7% percent, respectively. Within L1C domains, five amino acid residues (Leu-135, Gly-188, Arg-244, and vicinal His-318 and Lys-319) were identified as IRR-specific by species conservation analysis of the IR family. These residues are exposed and located in junctions between secondary structure folds. The quintuple mutation of these residues to alanine had the same negative effect as the entire L1C domain replacement, whereas none of the single mutations was as effective. Separate mutations of these five residues and of L2 produced partial negative effects that were additive. The pH dependence of cell-expressed mutants (L1C and L2 swap, L2 plus triple LGR mutation, and L2 plus quintuple LGRHK mutation) was shifted toward alkalinity and, in contrast with IRR, did not show significant positive cooperativity. Our data suggest that IRR activation is not based on a single residue deprotonation in the IRR ectodomain but rather involves synergistic conformational changes at multiple points.
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Deficient response to experimentally induced alkalosis in mice with the inactivated insrr gene
Acta naturae, 2011Co-Authors: Igor E Deyev, O. V. Serova, Nadezhda V. Popova, Anastasiya A. Berchatova, D I Rzhevsky, A N Murashev, A. G. PetrenkoAbstract:Currently, the molecular mechanisms of the acid-base equilibrium maintenance in the body remain poorly understood. The development of alkalosis under various pathological conditions poses an immediate threat to human life. Understanding the physiological mechanisms of alkalosis compensation may stimulate the development of new therapeutic approaches and new drugs for treatment. It was previously shown that the orphan Insulin Receptor-Related Receptor (IRR) is activated by mildly alkaline media. In this study, we analyzed mutant mice with targeted inactivation of theinsrr gene encoding IRR, and revealed their phenotype related to disorders of the acid-base equilibrium. Higher concentrations of bicarbonate and CO(2)were found in the blood ofinsrr knockout mice in response to metabolic alkalosis.
Igor E Deyev - One of the best experts on this subject based on the ideXlab platform.
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mapping of alkali sensing sites of the Insulin Receptor related Receptor the role of l2 and fibronectin domains
Biochimie, 2015Co-Authors: Igor E Deyev, N. A. Chachina, D. M. Shayahmetova, O. V. Serova, A. G. PetrenkoAbstract:Insulin Receptor-Related Receptor (IRR) is a member of the Insulin Receptor (IR) family that works as an extracellular alkali sensor with positive cooperativity. The pH sensing property of IRR is defined by its extracellular region and involves multiple domains. We have previously demonstrated the primary role of L1C domains and identified potentially important amino acid residues within these domains. In this study, we addressed the roles of L2 and FnIII domains. Within the L2 domain, five amino acid residues (M406, V407, D408, P436 and V437) were identified as IRR-specific by performing a species conservation analysis of the IR family. Single-point mutations of these five residues to alanine produced either little or no negative effect on IRR pH-sensing activity. However, the triple mutation of M406, V407 and D408 (MVD) showed a strong negative effect, with a 4 fold decrease in IRR activity as estimated by in vitro autophosphorylation assay of solubilized Receptors. The analysis of this mutant in intact cells revealed the absence of positive cooperativity. Unexpectedly, the double mutation of vicinal P436 and V437 (PV) exhibited a significant positive effect in the in vitro assay and partial positive cooperativity in the whole-cell assay. The role of FnIII domains was addressed by analyzing chimeras of IRR and IR. When the IRR FnIII domains were swapped with those of IR in different combinations, the activity was significantly reduced and positive cooperativity eliminated. However, two mutants with the targeted C-terminal part of IRR alpha subunit that lies within FnIII-2 domain and have been shown to be important for Insulin binding by IR, appeared to be as active as wild-type IRR. On the basis of available data, we propose that IRR activation involves two separate centers of pH-dependent rearrangements that act synergistically to induce a major conformational change in the IRR molecule, resulting in internal kinase domains rapprochement and autophosphorylation.
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Structural determinants of the Insulin Receptor-Related Receptor activation by alkali
The Journal of biological chemistry, 2013Co-Authors: Igor E Deyev, O. V. Serova, Nadezhda V. Popova, Anastasiya A. Berchatova, Egor S. Zhevlenev, Alla V. Mitrofanova, Nikita Radionov, A. G. PetrenkoAbstract:Abstract IRR is a member of the Insulin Receptor (IR) family that does not have any known agonist of a peptide nature but can be activated by mildly alkaline medium and was thus proposed to function as an extracellular pH sensor. IRR activation by alkali is defined by its N-terminal extracellular region. To reveal key structural elements involved in alkali sensing, we developed an in vitro method to quantify activity of IRR and its mutants. Replacing the IRR L1C domains (residues 1–333) or L2 domain (residues 334–462) or both with the homologous fragments of IR reduced the Receptor activity to 35, 64, and 7% percent, respectively. Within L1C domains, five amino acid residues (Leu-135, Gly-188, Arg-244, and vicinal His-318 and Lys-319) were identified as IRR-specific by species conservation analysis of the IR family. These residues are exposed and located in junctions between secondary structure folds. The quintuple mutation of these residues to alanine had the same negative effect as the entire L1C domain replacement, whereas none of the single mutations was as effective. Separate mutations of these five residues and of L2 produced partial negative effects that were additive. The pH dependence of cell-expressed mutants (L1C and L2 swap, L2 plus triple LGR mutation, and L2 plus quintuple LGRHK mutation) was shifted toward alkalinity and, in contrast with IRR, did not show significant positive cooperativity. Our data suggest that IRR activation is not based on a single residue deprotonation in the IRR ectodomain but rather involves synergistic conformational changes at multiple points.
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Deficient response to experimentally induced alkalosis in mice with the inactivated insrr gene
Acta naturae, 2011Co-Authors: Igor E Deyev, O. V. Serova, Nadezhda V. Popova, Anastasiya A. Berchatova, D I Rzhevsky, A N Murashev, A. G. PetrenkoAbstract:Currently, the molecular mechanisms of the acid-base equilibrium maintenance in the body remain poorly understood. The development of alkalosis under various pathological conditions poses an immediate threat to human life. Understanding the physiological mechanisms of alkalosis compensation may stimulate the development of new therapeutic approaches and new drugs for treatment. It was previously shown that the orphan Insulin Receptor-Related Receptor (IRR) is activated by mildly alkaline media. In this study, we analyzed mutant mice with targeted inactivation of theinsrr gene encoding IRR, and revealed their phenotype related to disorders of the acid-base equilibrium. Higher concentrations of bicarbonate and CO(2)were found in the blood ofinsrr knockout mice in response to metabolic alkalosis.
O. V. Serova - One of the best experts on this subject based on the ideXlab platform.
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mapping of alkali sensing sites of the Insulin Receptor related Receptor the role of l2 and fibronectin domains
Biochimie, 2015Co-Authors: Igor E Deyev, N. A. Chachina, D. M. Shayahmetova, O. V. Serova, A. G. PetrenkoAbstract:Insulin Receptor-Related Receptor (IRR) is a member of the Insulin Receptor (IR) family that works as an extracellular alkali sensor with positive cooperativity. The pH sensing property of IRR is defined by its extracellular region and involves multiple domains. We have previously demonstrated the primary role of L1C domains and identified potentially important amino acid residues within these domains. In this study, we addressed the roles of L2 and FnIII domains. Within the L2 domain, five amino acid residues (M406, V407, D408, P436 and V437) were identified as IRR-specific by performing a species conservation analysis of the IR family. Single-point mutations of these five residues to alanine produced either little or no negative effect on IRR pH-sensing activity. However, the triple mutation of M406, V407 and D408 (MVD) showed a strong negative effect, with a 4 fold decrease in IRR activity as estimated by in vitro autophosphorylation assay of solubilized Receptors. The analysis of this mutant in intact cells revealed the absence of positive cooperativity. Unexpectedly, the double mutation of vicinal P436 and V437 (PV) exhibited a significant positive effect in the in vitro assay and partial positive cooperativity in the whole-cell assay. The role of FnIII domains was addressed by analyzing chimeras of IRR and IR. When the IRR FnIII domains were swapped with those of IR in different combinations, the activity was significantly reduced and positive cooperativity eliminated. However, two mutants with the targeted C-terminal part of IRR alpha subunit that lies within FnIII-2 domain and have been shown to be important for Insulin binding by IR, appeared to be as active as wild-type IRR. On the basis of available data, we propose that IRR activation involves two separate centers of pH-dependent rearrangements that act synergistically to induce a major conformational change in the IRR molecule, resulting in internal kinase domains rapprochement and autophosphorylation.
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Structural determinants of the Insulin Receptor-Related Receptor activation by alkali
The Journal of biological chemistry, 2013Co-Authors: Igor E Deyev, O. V. Serova, Nadezhda V. Popova, Anastasiya A. Berchatova, Egor S. Zhevlenev, Alla V. Mitrofanova, Nikita Radionov, A. G. PetrenkoAbstract:Abstract IRR is a member of the Insulin Receptor (IR) family that does not have any known agonist of a peptide nature but can be activated by mildly alkaline medium and was thus proposed to function as an extracellular pH sensor. IRR activation by alkali is defined by its N-terminal extracellular region. To reveal key structural elements involved in alkali sensing, we developed an in vitro method to quantify activity of IRR and its mutants. Replacing the IRR L1C domains (residues 1–333) or L2 domain (residues 334–462) or both with the homologous fragments of IR reduced the Receptor activity to 35, 64, and 7% percent, respectively. Within L1C domains, five amino acid residues (Leu-135, Gly-188, Arg-244, and vicinal His-318 and Lys-319) were identified as IRR-specific by species conservation analysis of the IR family. These residues are exposed and located in junctions between secondary structure folds. The quintuple mutation of these residues to alanine had the same negative effect as the entire L1C domain replacement, whereas none of the single mutations was as effective. Separate mutations of these five residues and of L2 produced partial negative effects that were additive. The pH dependence of cell-expressed mutants (L1C and L2 swap, L2 plus triple LGR mutation, and L2 plus quintuple LGRHK mutation) was shifted toward alkalinity and, in contrast with IRR, did not show significant positive cooperativity. Our data suggest that IRR activation is not based on a single residue deprotonation in the IRR ectodomain but rather involves synergistic conformational changes at multiple points.
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Deficient response to experimentally induced alkalosis in mice with the inactivated insrr gene
Acta naturae, 2011Co-Authors: Igor E Deyev, O. V. Serova, Nadezhda V. Popova, Anastasiya A. Berchatova, D I Rzhevsky, A N Murashev, A. G. PetrenkoAbstract:Currently, the molecular mechanisms of the acid-base equilibrium maintenance in the body remain poorly understood. The development of alkalosis under various pathological conditions poses an immediate threat to human life. Understanding the physiological mechanisms of alkalosis compensation may stimulate the development of new therapeutic approaches and new drugs for treatment. It was previously shown that the orphan Insulin Receptor-Related Receptor (IRR) is activated by mildly alkaline media. In this study, we analyzed mutant mice with targeted inactivation of theinsrr gene encoding IRR, and revealed their phenotype related to disorders of the acid-base equilibrium. Higher concentrations of bicarbonate and CO(2)were found in the blood ofinsrr knockout mice in response to metabolic alkalosis.
Sergio R Ojeda - One of the best experts on this subject based on the ideXlab platform.
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expression of the Insulin Receptor related Receptor is induced by the preovulatory surge of luteinizing hormone in thecal interstitial cells of the rat ovary
Endocrinology, 2006Co-Authors: Gregory A Dissen, Luis F. Parada, Cecilia Garciarudaz, Veronica Tapia, Sheau Yu Teddy Hsu, Sergio R OjedaAbstract:The Insulin Receptor-Related Receptor (IRR) is a member of the Insulin Receptor family that, on its own, recognizes neither Insulin nor any of the identified Insulin-related peptides. In both the nervous system and peripheral tissues, IRR mRNA is detected in cells that also express trkA, the nerve growth factor tyrosine kinase Receptor. In the ovary, the trkA gene is transiently activated in thecal-interstitial cells of large antral follicles at the time of the preovulatory surge of gonadotropins. The present study shows that the IRR gene is expressed in the same ovarian compartment, that IRR mRNA content increases strikingly in these cells in the afternoon of the first proestrus, and that—as in the case of trkA mRNA—the increase is caused by gonadotropins. The IRR mRNA species primarily affected is that encoding the full-length Receptor; its increased abundance was accompanied by a corresponding change in IRR protein content. An extensive molecular search using several approaches, including the screening...
Veronica Tapia - One of the best experts on this subject based on the ideXlab platform.
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expression of the Insulin Receptor related Receptor is induced by the preovulatory surge of luteinizing hormone in thecal interstitial cells of the rat ovary
Endocrinology, 2006Co-Authors: Gregory A Dissen, Luis F. Parada, Cecilia Garciarudaz, Veronica Tapia, Sheau Yu Teddy Hsu, Sergio R OjedaAbstract:The Insulin Receptor-Related Receptor (IRR) is a member of the Insulin Receptor family that, on its own, recognizes neither Insulin nor any of the identified Insulin-related peptides. In both the nervous system and peripheral tissues, IRR mRNA is detected in cells that also express trkA, the nerve growth factor tyrosine kinase Receptor. In the ovary, the trkA gene is transiently activated in thecal-interstitial cells of large antral follicles at the time of the preovulatory surge of gonadotropins. The present study shows that the IRR gene is expressed in the same ovarian compartment, that IRR mRNA content increases strikingly in these cells in the afternoon of the first proestrus, and that—as in the case of trkA mRNA—the increase is caused by gonadotropins. The IRR mRNA species primarily affected is that encoding the full-length Receptor; its increased abundance was accompanied by a corresponding change in IRR protein content. An extensive molecular search using several approaches, including the screening...