Journal of Biological Chemistry
Volume 287, Issue 36, 31 August 2012, Pages 30128-30138
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Signal Transduction
Human Neuroglobin Functions as an Oxidative Stress-responsive Sensor for Neuroprotection*

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Mammalian neuroglobin (Ngb) protects neuronal cells under conditions of oxidative stress. The mechanism underlying this function is only partly understood. Here, we report that human Ngb exists in lipid rafts only during oxidative stress and that lipid rafts are crucial for neuroprotection by Ngb. The ferrous oxygen-bound form of Ngb, which exists under normoxia, is converted to the ferric bis-His conformation during oxidative stress, inducing large tertiary structural changes. We clarified that ferric bis-His Ngb, but not ferrous ligand-bound Ngb, specifically binds to flotillin-1, a lipid raft microdomain-associated protein, as well as to α-subunits of heterotrimeric G proteins (Gαi/o). Moreover, we found that human ferric bis-His Ngb acts as a guanine nucleotide dissociation inhibitor for Gαi/o that has been modified by oxidative stress. In addition, our data shows that Ngb inhibits the decrease in cAMP concentration that occurs under oxidative stress, leading to protection against cell death. Furthermore, by using a mutated Ngb protein that cannot form the bis-His conformation, we demonstrate that the oxidative stress-induced structural changes of human Ngb are essential for its neuroprotective activity.

Hemoglobin Myoglobin
Neuroprotection
Oxidative Stress
Protein-Protein Interactions
Signal Transduction

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*

This work was supported in part by the PRESTO program of Japan Science and Technology (JST) (to K. W.) and a Grant-in-Aid 23117704 for Scientific Research (to K. W.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

1

Supported by the JSPS Research Fellowships for Young Scientists. Present address: RIKEN Brain Science Institute, Wako, Saitama, Japan.