In this present study, we investigated the H2O2-induced oligomerization of wild-type human neuroglobin (hNgb) and of some selected variants (C46AC55A, Y44A, Y44F, Y44AC46AC55A, Y44AC46AC55A) to clarify how the process is affected by the Cys46/Cys55 disulfide bond and the distal H-bonding network and to figure out the molecular determinants of the H2O2-induced formation of amyloid-type structures and hNgb aggregates. It turns out that hydrogen peroxide exerts a two-fold effect on hNgb, inducing both heme breakdown and protein dimerization/polymerization. The enhanced resistance to the oxidizing effect of H2O2 of the disulfide-free variants indicates that both effects are strictly influenced by the heme accessibility for H2O2. Most importantly, the H2O2-induced neuroglobin dimerization/polymerization turns out to be triggered by tyrosyl radicals resulting from the oxidizing action of Compound I ([Por center dot Fe(IV) = O]+). Peptide mapping indicates that the H2O2-induced dimerization/polymerization of hNgb mainly involves Tyr44, which forms covalent bonds with all the other tyrosine residues, with a minor contribution from Tyr88. The presented findings contribute further important pieces of information in the quest of identifying all capabilities of hNgb and ultimately its physiological task.
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Univ Modena & Reggio Emilia, Dept Life Sci, Via Campi 103, I-41125 Modena, ItalyUniv Modena & Reggio Emilia, Dept Life Sci, Via Campi 103, I-41125 Modena, Italy
Di Rocco, Giulia
Bernini, Fabrizio
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Univ Modena & Reggio Emilia, Dept Chem & Geol Sci, Via Campi 103, I-41125 Modena, ItalyUniv Modena & Reggio Emilia, Dept Life Sci, Via Campi 103, I-41125 Modena, Italy
Bernini, Fabrizio
Battistuzzi, Gianantonio
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Univ Modena & Reggio Emilia, Dept Chem & Geol Sci, Via Campi 103, I-41125 Modena, ItalyUniv Modena & Reggio Emilia, Dept Life Sci, Via Campi 103, I-41125 Modena, Italy
Battistuzzi, Gianantonio
Ranieri, Antonio
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Univ Modena & Reggio Emilia, Dept Life Sci, Via Campi 103, I-41125 Modena, ItalyUniv Modena & Reggio Emilia, Dept Life Sci, Via Campi 103, I-41125 Modena, Italy
Ranieri, Antonio
Bortolotti, Carlo Augusto
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Univ Modena & Reggio Emilia, Dept Life Sci, Via Campi 103, I-41125 Modena, ItalyUniv Modena & Reggio Emilia, Dept Life Sci, Via Campi 103, I-41125 Modena, Italy
Bortolotti, Carlo Augusto
Borsari, Marco
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Univ Modena & Reggio Emilia, Dept Chem & Geol Sci, Via Campi 103, I-41125 Modena, ItalyUniv Modena & Reggio Emilia, Dept Life Sci, Via Campi 103, I-41125 Modena, Italy
Borsari, Marco
Sola, Marco
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Univ Modena & Reggio Emilia, Dept Chem & Geol Sci, Via Campi 103, I-41125 Modena, ItalyUniv Modena & Reggio Emilia, Dept Life Sci, Via Campi 103, I-41125 Modena, Italy
机构:
Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, JapanKyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan
Nakamura, Kuniyuki
Kamouchi, Masahiro
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Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, JapanKyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan
Kamouchi, Masahiro
Kitazono, Takanari
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Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, JapanKyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan
Kitazono, Takanari
Kuroda, Junya
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Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, JapanKyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan
Kuroda, Junya
Shono, Yuji
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Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, JapanKyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan
Shono, Yuji
Hagiwara, Noriko
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Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, JapanKyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan
Hagiwara, Noriko
Ago, Tetsuro
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Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, JapanKyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan
Ago, Tetsuro
Ooboshi, Hiroaki
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Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, JapanKyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan
Ooboshi, Hiroaki
Ibayashi, Setsuro
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Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, JapanKyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan
Ibayashi, Setsuro
Iida, Mitsuo
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Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, JapanKyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Higashi Ku, Fukuoka 8128582, Japan
机构:
Tuskegee Univ, Dept Biol, Tuskegee, AL 36088 USAAuburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USA
Shalgum, Aiman
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Govindarajulu, Manoj
Majrashi, Mohammed
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Auburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USA
Univ Jeddah, Fac Med, Dept Pharmacol, Jeddah, Saudi ArabiaAuburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USA
Majrashi, Mohammed
Ramesh, Sindhu
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Auburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USAAuburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USA
Ramesh, Sindhu
Collier, Willard E.
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Tuskegee Univ, Dept Biol, Tuskegee, AL 36088 USAAuburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USA
Collier, Willard E.
Griffin, Gerald
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Tuskegee Univ, Dept Biol, Tuskegee, AL 36088 USAAuburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USA
Griffin, Gerald
Amin, Rajesh
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Auburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USAAuburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USA
Amin, Rajesh
Bradford, Chastity
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Tuskegee Univ, Dept Biol, Tuskegee, AL 36088 USAAuburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USA
Bradford, Chastity
Moore, Timothy
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Auburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USAAuburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USA