Heme Binding
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2021 ◽  
Vol 448 ◽  
pp. 214189
Author(s):  
Brian J. Goodfellow ◽  
Filipe Freire ◽  
Ana Luísa Carvalho ◽  
Susana S. Aveiro ◽  
Peggy Charbonnier ◽  
...  

2021 ◽  
Author(s):  
Hannah L. Raczkowski ◽  
Li S. Xu ◽  
Wei Cen Wang ◽  
Rodney P DeKoter

Spi-C is an E26 transformation-specific transcription factor closely related to PU.1 and Spi-B. Spi-C has lineage-instructive functions important in antibody-generating responses, B cell development, and red pulp macrophage generation. Spi-C is inducible by heme- and NF-κB-dependent pathways in macrophages. The present research aimed to examine the regulation of Spi-C expression in B cells. RT-qPCR analysis revealed that Spic expression was reduced in B cells following addition of lipopolysaccharide, anti-IgM antibodies, CD40L, or cytokines BAFF + IL-4 + IL-5. Cytochalasin treatment partially prevented downregulation of Spic. Unstimulated B cells upregulated Spic over time in culture. To determine the mechanism of Spic regulation, we examined the Spic promoter and upstream regulatory elements. The Spic promoter had unidirectional activity, which was reduced by mutation of an NF-κB binding site. Spic was repressed by an upstream regulatory region interacting with the heme-binding regulator Bach2. Taken together, these data indicate that Spi-C is dynamically regulated by external signals in B cells and provide insight into the mechanism of regulation.


2021 ◽  
Author(s):  
Luke E Formosa ◽  
Shadi Maghool ◽  
Alice J. Sharpe ◽  
Boris Reljic ◽  
Linden Muellner-Wong ◽  
...  

Cytochrome c oxidase assembly factor 7 (COA7) is a metazoan-specific assembly factor, critical for the biogenesis of mitochondrial complex IV (cytochrome c oxidase). Although mutations in COA7 have been linked in patients to complex IV assembly defects and neurological conditions such as peripheral neuropathy, ataxia and leukoencephalopathy, the precise role COA7 plays in the biogenesis of complex IV is not known. Here we show that the absence of COA7 leads to arrest of the complex IV assembly pathway at the initial step where the COX1 module is built, which requires incorporation of copper and heme cofactors. In solution, purified COA7 binds heme with micromolar affinity, through axial ligation to the central iron atom by histidine and methionine residues. Surprisingly, the crystal structure of COA7, determined to 2.4 angstroms resolution, reveals a banana-shaped molecule composed of five helix-turn-helix repeats, tethered by disulfide bonds, with a structure entirely distinct from proteins with characterized heme binding activities. We therefore propose a role for COA7 in heme binding/chaperoning in the mitochondrial intermembrane space, this activity being crucial for and providing a missing link in complex IV biogenesis.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ritobrita Chakraborty ◽  
Sandip Dey ◽  
Pallabi Sil ◽  
Simanta Sarani Paul ◽  
Dipita Bhattacharyya ◽  
...  

AbstractThe fibrillation pathway of alpha-Synuclein, the causative protein of Parkinson’s disease, encompasses transient, heterogeneous oligomeric forms whose structural understanding and link to toxicity are not yet understood. We report that the addition of the physiologically-available small molecule heme at a sub-stoichiometric ratio to either monomeric or aggregated α-Syn, targets a His50 residue critical for fibril-formation and stabilizes the structurally-heterogeneous populations of aggregates into a minimally-toxic oligomeric state. Cryo-EM 3D reconstruction revealed a ‘mace’-shaped structure of this monodisperse population of oligomers, which is comparable to a solid-state NMR Greek key-like motif (where the core residues are arranged in parallel in-register sheets with a Greek key topology at the C terminus) that forms the fundamental unit/kernel of protofilaments. Further structural analyses suggest that heme binding induces a distortion in the Greek key-like architecture of the mace oligomers, which impairs their further appending into protofilaments and fibrils. Additionally, our study reports a novel mechanism of prevention as well as reclamation of amyloid fibril formation by blocking an inter-protofilament His50 residue using a small molecule.


2021 ◽  
Vol 118 (17) ◽  
pp. e2015689118
Author(s):  
Lijuan Zhao ◽  
Haibo Xie ◽  
Yunsi Kang ◽  
Yiwen Lin ◽  
Gai Liu ◽  
...  

Coordinated beating is crucial for the function of multiple cilia. However, the molecular mechanism is poorly understood. Here, we characterize a conserved ciliary protein CYB5D1 with a heme-binding domain and a cordon-bleu ubiquitin-like domain. Mutation or knockdown of Cyb5d1 in zebrafish impaired coordinated ciliary beating in the otic vesicle and olfactory epithelium. Similarly, the two flagella of an insertional mutant of the CYB5D1 ortholog in Chlamydomonas (Crcyb5d1) showed an uncoordinated pattern due to a defect in the cis-flagellum. Biochemical analyses revealed that CrCYB5D1 is a radial spoke stalk protein that binds heme only under oxidizing conditions. Lack of CrCYB5D1 resulted in a reductive shift in flagellar redox state and slowing down of the phototactic response. Treatment of Crcyb5d1 with oxidants restored coordinated flagellar beating. Taken together, these data suggest that CrCYB5D1 may integrate environmental and intraciliary signals and regulate the redox state of cilia, which is crucial for the coordinated beating of multiple cilia.


2021 ◽  
Author(s):  
Marie-T. Hopp ◽  
Daniel Domingo-Fernandez ◽  
Yojana Gadiya ◽  
Milena S. Detzel ◽  
Regina Graf ◽  
...  

Abstract The SARS-CoV-2 outbreak has been declared a worldwide pandemic in 2020. Infection triggers the respiratory tract disease COVID-19, which is accompanied by serious changes of clinical biomarkers such as hemoglobin and interleukins. The same parameters are altered during hemolysis, which is characterized by an increase in labile heme. We present two computational-experimental approaches that aim at analyzing a potential link between heme-related and COVID-19 pathophysiologies. Herein, we performed a detailed analysis of the common pathways induced by heme and SARS-CoV-2 by superimposition of knowledge graphs covering heme biology and COVID-19 pathophysiology. Focus was laid on inflammatory pathways and distinct biomarkers as the linking elements. In a second approach, four COVID-19-related proteins, the host cell proteins ACE2 and TMPRSS2 as well as the viral protein 7a and S protein, were computationally analyzed as potential heme-binding proteins with an experimental validation. The results contribute to the understanding of the progression of COVID-19 infections in patients with different clinical backgrounds and might allow for a more individual diagnosis and therapy in the future.


2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Milena Sophie Detzel ◽  
Benjamin Franz Schmalohr ◽  
Francèl Steinbock ◽  
Marie-Thérèse Hopp ◽  
Anuradha Ramoji ◽  
...  

Abstract In hemolytic disorders, erythrocyte lysis results in massive release of hemoglobin and, subsequently, toxic heme. Hemopexin is the major protective factor against heme toxicity in human blood and currently considered for therapeutic use. It has been widely accepted that hemopexin binds heme with extraordinarily high affinity of <1 pM in a 1:1 ratio. However, several lines of evidence point to a higher stoichiometry and lower affinity than determined 50 years ago. Here, we re-analyzed these data. SPR and UV/Vis spectroscopy were used to monitor the interaction of heme with the human protein. The heme-binding sites of hemopexin were characterized using hemopexin-derived peptide models and competitive displacement assays. We obtained a K D value of 0.32 ± 0.04 nM and the ratio for the interaction was determined to be 1:1 at low heme concentrations and at least 2:1 (heme:hemopexin) at high concentrations. We were able to identify two yet unknown potential heme-binding sites on hemopexin. Furthermore, molecular modelling with a newly created homology model of human hemopexin suggested a possible recruiting mechanism by which heme could consecutively bind several histidine residues on its way into the binding pocket. Our findings have direct implications for the potential administration of hemopexin in hemolytic disorders.


2021 ◽  
Vol 120 (3) ◽  
pp. 125a-126a
Author(s):  
Luis I. Gutierrez-Rus ◽  
Gloria Gamiz-Arco ◽  
Valeria A. Risso ◽  
Beatriz Ibarra-Molero ◽  
Yosuke Hoshino ◽  
...  

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