Pseudoperoxidase activity, conformational stability, and aggregation propensity of the His98Tyr myoglobin variant: implications for the onset of myoglobinopathy
| Autor: | Carlo Augusto Bortolotti, Marco Borsari, Stefan Hofbauer, Paul G. Furtmüller, Christian Obinger, Marcello Pignataro, Gianina Ravenscroft, Gianantonio Battistuzzi, Giulia Di Rocco, Marco Sola |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Hemeprotein Protein Conformation Mutant Cleavage (embryo) Biochemistry chemistry.chemical_compound Muscular Diseases myoglobinopathy Humans Histidine high-molecular weight aggregates Molecular Biology Heme conformational stability biology Myoglobin Chemistry Point mutation pseudoperoxidase Active site Hydrogen Peroxide Cell Biology heme bleaching myoglobin Mutation Biophysics biology.protein Oxygen binding myoglobin myoglobinopathy pseudoperoxidase heme bleaching conformational stability high-molecular weight aggregates |
| Zdroj: | The FEBS Journal. 289:1105-1117 |
| ISSN: | 1742-4658 1742-464X |
| DOI: | 10.1111/febs.16235 |
| Popis: | The autosomal dominant striated muscle disease myoglobinopathy is due to the single point mutation His98Tyr in human myoglobin (MB) [Olive et al. (2019) Nat Comm 10, 1396], the heme protein responsible for binding, storage, and controlled release of O2 in striated muscle. In order to understand the molecular basis of this disease, a comprehensive biochemical and biophysical study on wt MB and the variant H98Y has been performed. Although only small differences exist between the active site architectures of the two proteins, the mutant (a) exhibits an increased reactivity toward hydrogen peroxide, (b) exhibits a higher tendency to form high-molecular-weight aggregates, and (c) is more prone to heme bleaching, possibly as a consequence of the observed H2 O2 -induced formation of the Tyr98 radical close to the metal center. These effects add to the impaired oxygen binding capacity and faster heme dissociation of the H98Y variant compared with wt MB. As the above effects result from bond formation/cleavage events occurring at the distal and proximal heme sites, it appears that the molecular determinants of the disease are localized there. These findings set the basis for clarifying the onset of the cascade of chemical events that are responsible for the pathological symptoms of myoglobinopathy. |
| Databáze: | OpenAIRE |
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