Selective binding of RGMc/hemojuvelin, a key protein in systemic iron metabolism, to BMP-2 and neogenin
| العنوان: | Selective binding of RGMc/hemojuvelin, a key protein in systemic iron metabolism, to BMP-2 and neogenin |
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| المؤلفون: | David Kuninger, Peter Rotwein, Mahta Nili, Robin Kuns-Hashimoto |
| المصدر: | American Journal of Physiology-Cell Physiology. 294:C994-C1003 |
| بيانات النشر: | American Physiological Society, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Physiology, Iron, Bone Morphogenetic Protein 2, Plasma protein binding, Biology, GPI-Linked Proteins, medicine.disease_cause, Bone morphogenetic protein, Bone morphogenetic protein 2, Cell Line, Transforming Growth Factor beta, medicine, Humans, Protein Isoforms, Hemochromatosis Protein, Hemojuvelin, Mutation, Cell Membrane, Membrane Proteins, Repulsive guidance molecule, Cell Biology, medicine.disease, Juvenile hemochromatosis, Cell biology, Gene Expression Regulation, Biochemistry, Cell culture, Bone Morphogenetic Proteins, Hemochromatosis, Protein Binding |
| الوصف: | Juvenile hemochromatosis is a severe and rapidly progressing hereditary disorder of iron overload, and it is caused primarily by defects in the gene encoding repulsive guidance molecule c/hemojuvelin (RGMc/HJV), a recently identified protein that undergoes a complicated biosynthetic pathway in muscle and liver, leading to cell membrane-linked single-chain and heterodimeric species, and two secreted single-chain isoforms. RGMc modulates expression of the hepatic iron regulatory factor, hepcidin, potentially through effects on signaling by the bone morphogenetic protein (BMP) family of soluble growth factors. To date, little is known about specific pathogenic defects in disease-causing RGMc/HJV proteins. Here we identify functional abnormalities in three juvenile hemochromatosis-linked mutants. Using a combination of approaches, we first show that BMP-2 could interact in biochemical assays with single-chain RGMc species, and also could bind to cell-associated RGMc. Two mouse RGMc amino acid substitution mutants, D165E and G313V (corresponding to human D172E and G320V), also could bind BMP-2, but less effectively than wild-type RGMc, while G92V (human G99V) could not. In contrast, the membrane-spanning protein, neogenin, a receptor for the related molecule, RGMa, preferentially bound membrane-associated heterodimeric RGMc and was able to interact on cells only with wild-type RGMc and G92V. Our results show that different isoforms of RGMc/HJV may play unique physiological roles through defined interactions with distinct signaling proteins and demonstrate that, in some disease-linked RGMc mutants, these interactions are defective. |
| تدمد: | 1522-1563 0363-6143 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::828798d3d9541f7454b4fc524c3de8abTest https://doi.org/10.1152/ajpcell.00563.2007Test |
| رقم الانضمام: | edsair.doi.dedup.....828798d3d9541f7454b4fc524c3de8ab |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15221563 03636143 |
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