Hydrogen peroxide induces heme degradation and protein aggregation in human neuroglobin: roles of the disulfide bridge and hydrogen‐bonding in the distal heme cavity. (31st July 2022)

• Record Type: Journal Article
• Authors: Di Rocco, Giulia; Bernini, Fabrizio; Battistuzzi, Gianantonio; Ranieri, Antonio; Bortolotti, Carlo Augusto; Borsari, Marco; Sola, Marco
• Is Part Of: FEBS journal. Volume 290:Number 1(2023)
• Page Start: 148
• Page End: 161
• Publication Date: 2022-07-31
• Subjects: aggregation -- amyloid -- electronic and MCD spectroscopies -- fibril -- hydrogen peroxide -- neuroglobin; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.16581
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : In the present study, human neuroglobin (hNgb) was found to undergo H2 O2 ‐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 H2 O2 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. Abstract : Human neuroglobin (hNgb) undergoes H2 O2 ‐induced breakdown of the heme center at a much slower rate than 5‐coordinated globins. The activation barrier of the reaction is affected by the disulfide bond‐controlled accessibility of the heme site and by the residues at positions 44 and 67. In the presence of H2 O2, wild‐type and mutated hNgb form β‐amyloid aggregates producing globular structures. The C46A/C55A, Y44A, Y44F and Y44F/C46A/C55A variants yield potentially harmful fibrils.