Human neuroglobin functions as an oxidative stress-responsive sensor for neuroprotection.
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 (Gα(i/o)). Moreover, we found that human ferric bis-His Ngb acts as a guanine nucleotide dissociation inhibitor for Gα(i/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.
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Tokyo 153-8902, Japan.
Seiji
S
Watanabe
Nozomu
N
Takahashi
Hiroyuki
H
Uchida
Keisuke
K
Wakasugi
D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D005296:Ferrous Compounds / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D005914:Globins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000078787:Neuroglobin; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D016716:PC12 Cells; D051381:Rats
D005296:Ferrous Compounds; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; C106354:flotillins; D005914:Globins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C034236:ferrous oxide