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Pseudoperoxidase activity, conformational stability, and aggregation propensity of the His98Tyr myoglobin variant: implications for the onset of myoglobinopathy
Author(s) -
Hofbauer Stefan,
Pignataro Marcello,
Borsari Marco,
Bortolotti Carlo Augusto,
Di Rocco Giulia,
Ravenscroft Gianina,
Furtmüller Paul G.,
Obinger Christian,
Sola Marco,
Battistuzzi Gianantonio
Publication year - 2022
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.16235
Subject(s) - myoglobin , heme , chemistry , biophysics , point mutation , mutant , hemeprotein , molecular dynamics , dissociation (chemistry) , cleavage (geology) , biochemistry , stereochemistry , biology , enzyme , computational chemistry , paleontology , fracture (geology) , gene
The autosomal dominant striated muscle disease myoglobinopathy is due to the single point mutation His98Tyr in human myoglobin (MB), the heme protein responsible for binding, storage, and controlled release of O 2 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 H 2 O 2 ‐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.