The conserved Trp114 residue of thioredoxin reductase 1 has a redox sensor-like function triggering oligomerization and crosslinking upon oxidative stress related to cell death. Cell Death Dis 2015 Jan 22;6(1):e1616
Date
01/23/2015Pubmed ID
25611390Pubmed Central ID
PMC4669772DOI
10.1038/cddis.2014.574Scopus ID
2-s2.0-84927620824 (requires institutional sign-in at Scopus site) 48 CitationsAbstract
The selenoprotein thioredoxin reductase 1 (TrxR1) has several key roles in cellular redox systems and reductive pathways. Here we discovered that an evolutionarily conserved and surface-exposed tryptophan residue of the enzyme (Trp114) is excessively reactive to oxidation and exerts regulatory functions. The results indicate that it serves as an electron relay communicating with the FAD moiety of the enzyme, and, when oxidized, it facilitates oligomerization of TrxR1 into tetramers and higher multimers of dimers. A covalent link can also be formed between two oxidized Trp114 residues of two subunits from two separate TrxR1 dimers, as found both in cell extracts and in a crystal structure of tetrameric TrxR1. Formation of covalently linked TrxR1 subunits became exaggerated in cells on treatment with the pro-oxidant p53-reactivating anticancer compound RITA, in direct correlation with triggering of a cell death that could be prevented by antioxidant treatment. These results collectively suggest that Trp114 of TrxR1 serves a function reminiscent of an irreversible sensor for excessive oxidation, thereby presenting a previously unrecognized level of regulation of TrxR1 function in relation to cellular redox state and cell death induction.
Author List
Xu J, Eriksson SE, Cebula M, Sandalova T, Hedström E, Pader I, Cheng Q, Myers CR, Antholine WE, Nagy P, Hellman U, Selivanova G, Lindqvist Y, Arnér ESMESH terms used to index this publication - Major topics in bold
AnimalsCell Death
Cell Line, Tumor
Conserved Sequence
Cross-Linking Reagents
Flavin-Adenine Dinucleotide
Furans
HCT116 Cells
Humans
Kinetics
Masoprocol
Models, Molecular
Mutant Proteins
Oxidation-Reduction
Oxidative Stress
Protein Multimerization
Rats
Structure-Activity Relationship
Thioredoxin Reductase 1
Tryptophan
