Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells
| Autor: | Anuradha Bharara Singh, Ritu Chakravarti, Elizabeth A. Sweeny, Luciana Hannibal, Dennis J. Stuehr, Arushi Saini, Pablo D. Dans, Greer Garee, Osiris Martinez-Guzman, Amit R. Reddi, Mohammad Mahfuzul Haque |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Hemeprotein Heme binding Molecular Sequence Data Nitric Oxide Synthase Type II Heme Crystallography X-Ray Biochemistry 03 medical and health sciences chemistry.chemical_compound Mice Animals Humans Editors' Picks Hemeproteins Amino Acid Sequence Molecular Biology Transcription factor Glyceraldehyde 3-phosphate dehydrogenase Binding Sites 030102 biochemistry & molecular biology biology Chemistry Glyceraldehyde-3-Phosphate Dehydrogenases Cell Biology Cytosol 030104 developmental biology Chaperone (protein) biology.protein Sequence Alignment Molecular Chaperones Protein Binding |
| Popis: | Cellular heme is thought to be distributed between a pool of sequestered heme that is tightly bound within hemeproteins and a labile heme pool required for signaling and transfer into proteins. A heme chaperone that can hold and allocate labile heme within cells has long been proposed but never been identified. Here, we show that the glycolytic protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) fulfills this role by acting as an essential repository and allocator of bioavailable heme to downstream protein targets. We identified a conserved histidine in GAPDH that is needed for its robust heme binding both in vitro and in mammalian cells. Substitution of this histidine, and the consequent decreases in GAPDH heme binding, antagonized heme delivery to both cytosolic and nuclear hemeprotein targets, including inducible nitric-oxide synthase (iNOS) in murine macrophages and the nuclear transcription factor Hap1 in yeast, even though this GAPDH variant caused cellular levels of labile heme to rise dramatically. We conclude that by virtue of its heme-binding property, GAPDH binds and chaperones labile heme to create a heme pool that is bioavailable to downstream proteins. Our finding solves a fundamental question in cell biology and provides a new foundation for exploring heme homeostasis in health and disease. |
| Databáze: | OpenAIRE |
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