Formation of protein cross-links by singlet oxygen-mediated disulfide oxidation

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...

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Vydané v:Redox biology Ročník 41; s. 101874
Hlavní autori: Jiang, Shuwen, Carroll, Luke, Mariotti, Michele, Hägglund, Per, Davies, Michael J.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Netherlands Elsevier B.V 01.05.2021
Elsevier
Predmet:
Disulfide
Photo-oxidation
Post-translational modification
Protein aggregation
Protein cross-links
Research Paper
Singlet oxygen
Thiol-disulfide exchange
Post-translational modification
CRP
Protein aggregation
DTT
LYSO
Thiol-disulfide exchange
ACN
TFA
PDB
RB
Singlet oxygen
Photo-oxidation
IAM
PBST
Disulfide
aLA
NEM
FA
B2M
GAPDH
TCEP
Protein cross-links
ISSN:2213-2317, 2213-2317
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Popis
Shrnutí: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 (1O2)-mediated oxidation of multiple proteins (α-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 1O2 concentration, the presence of the original protein disulfide bond, and the free Cys on GAPDH. MS with 18O-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. [Display omitted] •Disulfide bonds (DSBs) are critical to protein structure and function.•DSBs are rapidly oxidized by singlet oxygen and other oxidants to reactive intermediates.•These intermediates react with Cys-containing proteins to give new protein-protein cross-links.•This novel disulfide cross-linking pathway affects the functional activity of the proteins.•These cross-links can be diminished by reductants, but this does not repair the DSB damage.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:2213-2317
2213-2317
DOI:10.1016/j.redox.2021.101874