Abstract:
: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.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
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 ESdoi
10.1038/cddis.2014.574subject
Has Abstractpub_date
2015-01-22 00:00:00pages
e1616issn
2041-4889pii
cddis2014574journal_volume
6pub_type
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