RRC ID 43950
Author Watanabe S, Takahashi N, Uchida H, Wakasugi K.
Title Human neuroglobin functions as an oxidative stress-responsive sensor for neuroprotection.
Journal J Biol Chem
Abstract 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.
Volume 287(36)
Pages 30128-38
Published 2012-8-31
DOI 10.1074/jbc.M112.373381
PII S0021-9258(20)63117-9
PMID 22787149
PMC PMC3436268
MeSH Animals Cell Hypoxia / genetics Ferrous Compounds / metabolism GTP-Binding Protein alpha Subunits, Gi-Go / genetics GTP-Binding Protein alpha Subunits, Gi-Go / metabolism Globins / genetics Globins / metabolism* Humans Membrane Microdomains / genetics Membrane Microdomains / metabolism* Membrane Microdomains / pathology Membrane Proteins / genetics Membrane Proteins / metabolism Mutation Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism* Neuroglobin Neurons / metabolism* Neurons / pathology Oxidative Stress* PC12 Cells Rats
IF 4.238
Times Cited 36
Human and Animal Cells PC-12(RCB0009)