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Hydrogen peroxide induces heme degradation and protein aggregation in human neuroglobin: roles of the disulfide bridge and hydrogen‐bonding in the distal heme cavity
Author(s) -
Di Rocco Giulia,
Bernini Fabrizio,
Battistuzzi Gianantonio,
Ranieri Antonio,
Bortolotti Carlo Augusto,
Borsari Marco,
Sola Marco
Publication year - 2023
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.16581
Subject(s) - heme , chemistry , neuroglobin , globin , covalent bond , kinetics , hydrogen bond , biophysics , histidine , hydrogen peroxide , hemeprotein , myoglobin , photochemistry , stereochemistry , biochemistry , amino acid , molecule , hemoglobin , organic chemistry , physics , quantum mechanics , biology , enzyme
In the present study, human neuroglobin (hNgb) was found to undergo H 2 O 2 ‐induced breakdown of the heme center at a much slower rate than other globins, namely in the timescale of hours against minutes. We investigated how the rate of the process is affected by the Cys46/Cys55 disulfide bond and the network of non‐covalent interactions in the distal heme side involving Tyr44, Lys67, the His64 heme iron axial ligand and the heme propionate‐7. The rate is increased by the Tyr44 to Ala and Phe mutations; however the rate is lowered by Lys67 to Ala swapping. The absence of the disulfide bridge slows down the reaction further. Therefore, the disulfide bond‐controlled accessibility of the heme site and the residues at position 44 and 67 affect the activation barrier of the reaction. Wild‐type and mutated species form β‐amyloid aggregates in the presence of H 2 O 2 producing globular structures. Furthermore, the C46A/C55A, Y44A, Y44F and Y44F/C46A/C55A variants yield potentially harmful fibrils. Finally, the nucleation and growth kinetics for the aggregation of the amyloid structures can be successfully described by the Finke–Watzky model.