High-affinity binding and catalytic activity of His/Tyr-based sequences: Extending heme-regulatory motifs beyond CP

Syllwasschy, Benjamin Franz; Beck, Maximilian Steve; Družeta, Ivona; Hopp, Marie-Thérèse; Ramoji, Anuradha; Neugebauer, Ute; Nozinovic, Senada; Menche, Dirk; Willbold, Dieter; Ohlenschläger, Oliver; Kühl, Toni; Imhof, Diana

doi:10.1016/j.bbagen.2020.129603

Cited by 23 publications

(49 citation statements)

References 60 publications

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“…Within the scavenger receptor cysteine-rich domain of the enzyme (Mendes de Oliveira et al, 2018), the interesting motif KKLYH 227 SDAC was found. It features an YH motif of intermediate hemebinding affinity on peptide level, however, of markedly improved affinity on the protein level as earlier demonstrated for IL-36 (Wißbrock et al, 2019;Syllwasschy et al, 2020). Furthermore, it shows high net charge and a hydrophobic leucine, which likely leads to high heme-binding affinity.…”

Section: Heme-binding Ability Of Surface Proteins Of Sars-cov-2 and Hmentioning

confidence: 52%

Unravelling the debate on heme effects in COVID-19 infections

Hopp

Domingo‐Fernándéz

Gadiya

et al. 2020

Preprint

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The SARS-CoV-2 outbreak was recently declared a worldwide pandemic. 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 approaches that aim at analyzing a potential link between available heme and COVID-19 pathogenesis. Four COVID-19 related proteins, i.e. the host cell proteins ACE2 and TMPRSS2 as well as the viral protein 7a and S protein, were identified as potential heme binders. We also 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. Herein, focus was laid on inflammatory pathways, and distinct biomarkers as the linking elements. Finally, the results substantially improve our understanding of COVID-19 infections and disease progression of patients with different clinical backgrounds and expand the diagnostic and treatment options.

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Section: Heme-binding Ability Of Surface Proteins Of Sars-cov-2 and Hmentioning

confidence: 52%

Unravelling the debate on heme effects in COVID-19 infections

Hopp

Domingo‐Fernándéz

Gadiya

et al. 2020

Preprint

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“…Consequently, UV/Vis shifts of all histidine-based heme-binding sites overlap and form one maximum. A nonlinear fit of the data 32 revealed a stoichiometry of 2:1 (heme:hemopexin) for this interaction and a K D value of 3.53 ± 0.80 μM, which represents a mixed value for all binding sites. These results substantiate the binding behaviour observed in SPR, as well as that of previous reports, in which the isolated N-terminal hemopexin domain, which lacks the confirmed binding site around H236/H293, binds heme 21,23 .…”

Section: Resultsmentioning

confidence: 94%

“…The heme-binding amino acids H236 and H238 are contained in two peptides of this study. Indeed, these residues might be considered a HXH motif 32 . While peptide H236 was a moderate binder, the motif H238 displayed high heme-binding affinity (RGHG H RNGT, K D = 0.35 ± 0.17 μM).…”

Section: Resultsmentioning

confidence: 99%

“…Heme stock solutions were prepared at 1 mM concentration as described earlier 37 , and freshly diluted in buffer immediately before usage. Heme concentrations were normalized using an extinction coefficient of 32.482 mM -1 cm -1 (398 nm) in HEPES 32 . Evaluation of the UV/Vis spectra was performed as described earlier using PRISM 7, GraphPad Software 37 .…”

Section: Methodsmentioning

confidence: 99%

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Revisiting the interaction of heme with hemopexin: Recommendations for the responsible use of an emerging drug

Detzel

Syllwasschy

Steinbock

et al. 2020

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“…However, we have recently identified potential new HRMs based on histidine and tyrosine, e.g. HXH, HXXXY, and HXXXH (20,21). The concept of heme binding to JAK2 is conceivable since the cells in which it is expressed, such as erythroid precursor cells, exhibit high heme concentrations (22,23).…”

Section: Introductionmentioning

confidence: 99%

Structural insights into the interaction of heme with protein tyrosine kinase JAK2

Schmalohr

Mustafa

Krämer

et al. 2020

Preprint

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Janus kinase 2 (JAK2) is the most important signal transducing tyrosine kinase in erythropoietic precursor cells. Its malfunction drives several myeloproliferative disorders. Heme is a small metal ion-carrying molecule, which is incorporated into hemoglobin in erythroid precursor cells to transport oxygen. In addition, heme is a signaling molecule and regulator of various biochemical processes. Here we show that heme exposure leads to hyperphosphorylation of JAK2 in a myeloid cancer cell line. Two peptides identified in JAK2 represent heme-regulatory motifs and show low micromolar affinities for heme. These peptides map to the kinase domain of JAK2, which is essential for downstream signaling. We suggest these motifs to be the interaction sites of heme with JAK2, which drive the heme-induced hyperphosphorylation. The results presented herein may facilitate the development of heme-related pharmacological tools to combat myeloproliferative disorders.

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High-affinity binding and catalytic activity of His/Tyr-based sequences: Extending heme-regulatory motifs beyond CP

Cited by 23 publications

References 60 publications

Unravelling the debate on heme effects in COVID-19 infections

Unravelling the debate on heme effects in COVID-19 infections

Revisiting the interaction of heme with hemopexin: Recommendations for the responsible use of an emerging drug

Structural insights into the interaction of heme with protein tyrosine kinase JAK2

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