PMID- 33601275
OWN - NLM
STAT- MEDLINE
DCOM- 20210705
LR  - 20210705
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 41
DP  - 2021 May
TI  - Formation of protein cross-links by singlet oxygen-mediated disulfide oxidation.
PG  - 101874
LID - S2213-2317(21)00022-7 [pii]
LID - 10.1016/j.redox.2021.101874 [doi]
LID - 101874
AB  - Cross-links formed within and between proteins are a major cause of protein 
      dysfunction, and are postulated to drive the accumulation of protein aggregates 
      in some human pathologies. Cross-links can be formed from multiple residues and 
      can be reversible (usually sulfur-sulfur bonds) or irreversible (typically 
      carbon-carbon or carbon-heteroatom bonds). Disulfides formed from oxidation of 
      two Cys residues are widespread, with these formed both deliberately, via 
      enzymatic reactions, or as a result of unintended oxidation reactions. We have 
      recently demonstrated that new protein-glutathione mixed disulfides can be formed 
      through oxidation of a protein disulfide to a thiosulfinate, and subsequent 
      reaction of this species with glutathione. Here we investigate whether similar 
      reactions occur between an oxidized protein disulfide, and a Cys residues on a 
      second protein, to give novel protein cross-links. Singlet oxygen 
      ((1)O(2))-mediated oxidation of multiple proteins (alpha-lactalbumin, lysozyme, 
      beta-2-microglobulin, C-reactive protein), and subsequent incubation with the 
      Cys-containing protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 
      generates inter-protein cross-links as detected by SDS-PAGE, immunoblotting and 
      mass spectrometry (MS). The cross-link yield is dependent on the (1)O(2) 
      concentration, the presence of the original protein disulfide bond, and the free 
      Cys on GAPDH. MS with (18)O-labeling has allowed identification of the residues 
      involved in some cases (e.g. Cys25 from the Cys25-Cys80 disulfide in 
      beta-2-microglobulin, with Cys149 or Cys244 of GAPDH). The formation of these 
      cross-links results in a loss of GAPDH enzymatic activity. These data provide 
      'proof-of-concept' for a novel mechanism of protein cross-link formation which 
      may help rationalize the accumulation of cross-linked proteins in multiple human 
      pathologies.
CI  - Copyright (c) 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Jiang, Shuwen
AU  - Jiang S
AD  - Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 
      Denmark.
FAU - Carroll, Luke
AU  - Carroll L
AD  - Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 
      Denmark.
FAU - Mariotti, Michele
AU  - Mariotti M
AD  - Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 
      Denmark.
FAU - Hagglund, Per
AU  - Hagglund P
AD  - Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 
      Denmark.
FAU - Davies, Michael J
AU  - Davies MJ
AD  - Department of Biomedical Sciences, Panum Institute, University of Copenhagen, 
      Denmark. Electronic address: davies@sund.ku.dk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210123
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (Disulfides)
RN  - 0 (Proteins)
RN  - 17778-80-2 (Singlet Oxygen)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - *Disulfides
MH  - Glutathione/metabolism
MH  - Humans
MH  - Oxidation-Reduction
MH  - Proteins
MH  - *Singlet Oxygen
PMC - PMC7900768
OTO - NOTNLM
OT  - Disulfide
OT  - Photo-oxidation
OT  - Post-translational modification
OT  - Protein aggregation
OT  - Protein cross-links
OT  - Singlet oxygen
OT  - Thiol-disulfide exchange
COIS- The authors declare no conflicts of interest with regard to the data presented.
EDAT- 2021/02/19 06:00
MHDA- 2021/07/06 06:00
PMCR- 2021/01/23
CRDT- 2021/02/18 20:18
PHST- 2020/12/06 00:00 [received]
PHST- 2021/01/05 00:00 [revised]
PHST- 2021/01/12 00:00 [accepted]
PHST- 2021/02/19 06:00 [pubmed]
PHST- 2021/07/06 06:00 [medline]
PHST- 2021/02/18 20:18 [entrez]
PHST- 2021/01/23 00:00 [pmc-release]
AID - S2213-2317(21)00022-7 [pii]
AID - 101874 [pii]
AID - 10.1016/j.redox.2021.101874 [doi]
PST - ppublish
SO  - Redox Biol. 2021 May;41:101874. doi: 10.1016/j.redox.2021.101874. Epub 2021 Jan 
      23.