NDLI: Active site cysteine-null glyceraldehyde-3-phosphate dehydrogenase (GAPDH) rescues nitric oxide-induced cell death

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Active site cysteine-null glyceraldehyde-3-phosphate dehydrogenase (GAPDH) rescues nitric oxide-induced cell death

Content Provider	Scilit
Author	Kubo, Takeya Nakajima, Hidemitsu Nakatsuji, Masatoshi Itakura, Masanori Kaneshige, Akihiro Azuma, Yasu-Taka Inui, Takashi Takeuchi, Tadayoshi
Copyright Year	2016
Description	Journal: Nitric Oxide Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a homotetrameric enzyme involved in a key step of glycolysis, also has a role in mediating cell death under nitrosative stress. Our previous reports suggest that nitric oxide-induced intramolecular disulfide-bonding GAPDH aggregation, which occurs through oxidation of the active site cysteine (Cys-152), participates in a mechanism to account for nitric oxide-induced death signaling in some neurodegenerative/neuropsychiatric disorders. Here, we demonstrate a rescue strategy for nitric oxide-induced cell death accompanied by GAPDH aggregation in a mutant with a substitution of Cys-152 to alanine (C152A-GAPDH). Pre-incubation of purified wild-type GAPDH with C152A-GAPDH under exposure to nitric oxide inhibited wild-type GAPDH aggregation in a concentration-dependent manner in vitro. Several lines of structural analysis revealed that C152A-GAPDH extensively interfered with nitric oxide-induced GAPDH-amyloidogenesis. Overexpression of doxycycline-inducible C152A-GAPDH in SH-SY5Y neuroblastoma significantly rescued nitric oxide-induced death, concomitant with the decreased formation of GAPDH aggregates. Further, both co-immunoprecipitation assays and simulation models revealed a heterotetramer composed of one dimer each of wild-type GAPDH and C152A-GAPDH. These results suggest that the C152A-GAPDH mutant acts as a dominant-negative molecule against GAPDH aggregation via the formation of this GAPDH heterotetramer. This study may contribute to a new therapeutic approach utilizing C152A-GAPDH against brain damage in nitrosative stress-related disorders
Related Links	https://core.ac.uk/download/pdf/82600653.pdf
Ending Page	21
Page Count	9
Starting Page	13
ISSN	10898603
e-ISSN	10898611
DOI	10.1016/j.niox.2015.12.005
Journal	Nitric Oxide
Volume Number	53
Language	English
Publisher	Elsevier BV
Publisher Date	2016-02-01
Access Restriction	Open
Subject Keyword	Journal: Nitric Oxide Biochemistry and Molecular Biology Nitric Oxide Protein Aggregation
Content Type	Text
Resource Type	Article
Subject	Physiology Clinical Biochemistry Biochemistry Cancer Research

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