PMID- 35562998
OWN - NLM
STAT- MEDLINE
DCOM- 20220517
LR  - 20230916
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 9
DP  - 2022 Apr 21
TI  - Mechanism of GAPDH Redox Signaling by H(2)O(2) Activation of a Two-Cysteine 
      Switch.
LID - 10.3390/ijms23094604 [doi]
LID - 4604
AB  - Oxidation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by reactive oxygen 
      species such as H(2)O(2) activate pleiotropic signaling pathways is associated 
      with pathophysiological cell fate decisions. Oxidized GAPDH binds chaperone 
      proteins with translocation of the complex to the nucleus and mitochondria 
      initiating autophagy and cellular apoptosis. In this study, we establish the 
      mechanism by which H(2)O(2)-oxidized GAPDH subunits undergo a subunit 
      conformational rearrangement. H(2)O(2) oxidizes both the catalytic cysteine and a 
      vicinal cysteine (four residues downstream) to their respective sulfenic acids. A 
      'two-cysteine switch' is activated, whereby the sulfenic acids irreversibly 
      condense to an intrachain thiosulfinic ester resulting in a major metastable 
      subunit conformational rearrangement. All four subunits of the homotetramer are 
      uniformly and independently oxidized by H(2)O(2), and the oxidized homotetramer 
      is stabilized at low temperatures. Over time, subunits unfold forming 
      disulfide-linked aggregates with the catalytic cysteine oxidized to a sulfinic 
      acid, resulting from thiosulfinic ester hydrolysis via the highly reactive 
      thiosulfonic ester intermediate. Molecular Dynamic Simulations provide additional 
      mechanistic insights linking GAPDH subunit oxidation with generating a putative 
      signaling conformer. The low-temperature stability of the H(2)O(2)-oxidized 
      subunit conformer provides an operable framework to study mechanisms associated 
      with gain-of-function activities of oxidized GAPDH to identify novel targets for 
      the treatment of neurodegenerative diseases.
FAU - Hyslop, Paul A
AU  - Hyslop PA
AUID- ORCID: 0000-0002-4831-1313
AD  - Arkley Research Labs, Arkley BioTek, LLC, 4444 Decatur Blvd., Indianapolis, IN 
      46241, USA.
FAU - Chaney, Michael O
AU  - Chaney MO
AD  - Eli Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, 
      USA.
LA  - eng
PT  - Journal Article
DEP - 20220421
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Esters)
RN  - 0 (Sulfenic Acids)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 1.2.1.- (Glyceraldehyde-3-Phosphate Dehydrogenases)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - *Cysteine/metabolism
MH  - Esters
MH  - Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism
MH  - Hydrogen Peroxide
MH  - Oxidation-Reduction
MH  - *Sulfenic Acids/metabolism
PMC - PMC9102624
OTO - NOTNLM
OT  - Molecular Dynamic Simulation
OT  - glyceraldehyde-3-phosphate dehydrogenase
OT  - hydrogen peroxide
OT  - neurodegenerative disease
OT  - oxidative stress
OT  - redox signaling
OT  - thiosulfinic ester
OT  - thiosulfonic ester
OT  - two-cysteine redox switch
COIS- The authors declare no conflict of interest.
EDAT- 2022/05/15 06:00
MHDA- 2022/05/18 06:00
PMCR- 2022/04/21
CRDT- 2022/05/14 01:02
PHST- 2022/03/14 00:00 [received]
PHST- 2022/04/13 00:00 [revised]
PHST- 2022/04/14 00:00 [accepted]
PHST- 2022/05/14 01:02 [entrez]
PHST- 2022/05/15 06:00 [pubmed]
PHST- 2022/05/18 06:00 [medline]
PHST- 2022/04/21 00:00 [pmc-release]
AID - ijms23094604 [pii]
AID - ijms-23-04604 [pii]
AID - 10.3390/ijms23094604 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Apr 21;23(9):4604. doi: 10.3390/ijms23094604.