Abstract

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 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 H2O2‐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.

Highlights

  • Myoglobin (MB) and its partner in O2 transport, hemoglobin, have been studied intensively for decades [1]

  • Beyond the two major roles—storage and facilitation of O2 diffusion in the heart and skeletal muscle—recent studies revealed that MB may protect the cell against reactive oxygen species (ROS) [2] and regulates NO homeostasis, but can have detrimental effects depending on tissue oxygen partial pressure and ROS availability [1,3,4,5]

  • The parameters for the H98Y variant are as follows: g1 = g2 = 5.913, g3 = 1.995; gstrain1 = gstrain2 = 0.2, gstrain3 = 0.14; rhombicity = 0%. These simulations show very minor differences of the electron distribution of the heme iron, which is mainly reflected in the peak width

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Summary

Introduction

Myoglobin (MB) and its partner in O2 transport, hemoglobin, have been studied intensively for decades [1]. Beyond the two major roles—storage and facilitation of O2 diffusion in the heart and skeletal muscle—recent studies revealed that MB may protect the cell against reactive oxygen species (ROS) [2] and regulates NO homeostasis, but can have detrimental effects depending on tissue oxygen partial pressure and ROS availability [1,3,4,5] This variety of roles is Abbreviations EGFP, enhanced green fluorescent protein; GSH, glutathione; HEK cells, human embryonic kidney cells; MALS, multi-angle static light scattering; MB, human myoglobin; PDA, photodiode-array detection; ROS, reactive oxygen species; SEC, size-exclusion chromatography; swMB, sperm whale myoglobin. The FEBS Journal published by John Wiley & Sons Ltd on behalf of

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