Non-Canonical Heme-Binding Proteins

Hannibal, Luciana; Stuehr, Dennis J.

doi:10.1142/9789814407755_0039

Cited by 2 publications

(2 citation statements)

References 140 publications

(254 reference statements)

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“…This behavior is consistent with GAPDH functioning as an intermediary, with its heme-binding affinity poised to be in equilibrium with an upstream heme source, while being lower than the heme affinities of the downstream protein delivery targets. In this regard, our estimate of the hGAPDH heme-binding affinity (K d of 1.5 ϫ 10 Ϫ7 M) derived from the k on and k off measures is similar to the heme K d value estimated for rGAPDH (12), and it is poorer than the heme K d values reported for hemeproteins like hemoglobin, myoglobin, eIF2␣, and others (20). The GAPDH heme K d is also consistent with the recent estimate of the labile heme concentration in cells that was determined using the fluorescent heme sensor that we used here (8).…”

Section: Gapdh Is a Chaperone That Controls Bioavailable Hemesupporting

confidence: 53%

Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells

Sweeny

Singh

Chakravarti

et al. 2018

Journal of Biological Chemistry

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106

140

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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 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.

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Section: Gapdh Is a Chaperone That Controls Bioavailable Hemesupporting

confidence: 53%

Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells

Sweeny

Singh

Chakravarti

et al. 2018

Journal of Biological Chemistry

Self Cite

106

140

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“…Moreover, the Tpx1 hemin-binding affinity is relatively moderate as compared to heme affinities of other intracellular hemeproteins that exhibit higher heme K D values such as Dap1, Cyb5, and Cyt1 proteins (Hannibal & Stuehr, 2013;Thompson et al, 2007). This observation may suggest an allocator role for Tpx1 in heme distribution to other intracellular target hemeproteins.…”

Section: Discussionmentioning

confidence: 93%

Hemeprotein Tpx1 interacts with cell‐surface heme transporter Str3 in Schizosaccharomyces pombe

Normant

Brault

Avino

et al. 2020

Molecular Microbiology

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Str3 is a transmembrane protein that mediates low-affinity heme uptake in Schizosaccharomyces pombe. Under iron-limiting conditions, Str3 remains at the cell surface in the presence of increasing hemin concentrations. Using a proximitydependent biotinylation approach coupled to mass spectrometry and coimmunoprecipitation assays, we report that the peroxiredoxin Tpx1 is a binding partner of Str3.Under microaerobic conditions, cells deficient in heme biosynthesis and lacking the heme receptor Shu1 exhibit poor hemin-dependent growth in the absence of Tpx1.Analysis of membrane protein preparations from iron-starved hem1Δ shu1Δ str3Δ tpx1Δ cells coexpressing Str3-GFP and TAP-Tpx1 showed that TAP-Tpx1 is enriched in membrane protein fractions in response to hemin. Bimolecular fluorescence complementation assays brought additional evidence that an interaction between Tpx1 and Str3 occurs at the plasma membrane. Results showed that Tpx1 exhibits an equilibrium constant value of 0.26 μM for hemin. The association of Tpx1 with hemin protects hemin from degradation by H 2 O 2 . The peroxidase activity of hemin is lowered when it is bound to Tpx1. Taken together, these results revealed that Tpx1 is a novel interacting partner of Str3. Our data are the first example of an interaction between a cytoplasmic heme-binding protein and a cell-surface heme transporter.

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Non-Canonical Heme-Binding Proteins

Cited by 2 publications

References 140 publications

Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells

Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells

Hemeprotein Tpx1 interacts with cell‐surface heme transporter Str3 in Schizosaccharomyces pombe

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