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Impact of A90P, F106L and H64V mutations on neuroglobin stability and ligand binding kinetics

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Abstract

Human neuroglobin (Ngb) is a hexacoordinated globin which binds some small ligands. Its function is still not well-established, even though Ngb seems to be implicated in the protection against neurodegenerative diseases. It has been shown by molecular dynamics and crystallography that ligand binding could occur thanks to a haem sliding mechanism specific to Ngb. In this paper, we studied some regions which could participate in this mechanism. We used UV–visible spectroscopy, CD and NMR to have a look on the protein structure and NMR and stopped-flow to study the ligand binding properties of the proteins. In the haem environment we mutated the distal histidine H64, the alanine A90 which is on the proximal F helix and the phenylalanine F106 which is close to the haem. We showed that both H64V and A90P variants, which affect the haem coordination, seemed to be important to haem and protein secondary structure stabilities whereas F106L mutation did not affect those properties. Then we confirmed that the cyanide binding kinetics were isomer dependent on wild-type Ngb and A90P and F106L variants. H64V Ngb variant had a behavior similar to wild-type Mb or Hb with a loss of the haem kinetic differentiation. Moreover, our results suggested that one haem isomer was more sensitive to A90P and F106L mutations. Those results brought some evidence that the haem sliding mechanism could occur for the cyanide binding and could be haem isomer dependent. The isomer forms may play distinct roles for the potential function of Ngb in vivo.

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Authors and Affiliations

  1. Laboratoire de Chimie-Physique, CNRS, Univ. Paris-Sud, Université Paris Saclay, 91405, Orsay, France

    E. André, V. Derrien, P. Sebban & S. Bernad

  2. Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Univ. Paris-Sud, Université Paris-Saclay, 1 Av. de la Terrasse, 91198, Gif-sur-Yvette, France

    N. Assrir & E. Lescop

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  1. E. André
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  2. V. Derrien
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  3. P. Sebban
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  4. N. Assrir
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  5. E. Lescop
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  6. S. Bernad
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Correspondence to E. André or S. Bernad.

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André, E., Derrien, V., Sebban, P. et al. Impact of A90P, F106L and H64V mutations on neuroglobin stability and ligand binding kinetics. J Biol Inorg Chem 24, 39–52 (2019). https://doi.org/10.1007/s00775-018-1625-x

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  • DOI: https://doi.org/10.1007/s00775-018-1625-x

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