Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells. J Biol Chem 2018 Sep 14;293(37):14557-14568
Date
07/18/2018Pubmed ID
30012884Pubmed Central ID
PMC6139559DOI
10.1074/jbc.RA118.004169Scopus ID
2-s2.0-85053291002 (requires institutional sign-in at Scopus site) 84 CitationsAbstract
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.
Author List
Sweeny EA, Singh AB, Chakravarti R, Martinez-Guzman O, Saini A, Haque MM, Garee G, Dans PD, Hannibal L, Reddi AR, Stuehr DJAuthor
Elizabeth Sweeny PhD Assistant Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Binding Sites
Crystallography, X-Ray
Glyceraldehyde-3-Phosphate Dehydrogenases
Heme
Humans
Mice
Molecular Chaperones
Molecular Sequence Data
Nitric Oxide Synthase Type II
Protein Binding
Sequence Alignment
