AI Article Synopsis
- ASK1 is an important enzyme involved in various diseases, and its activity is regulated by the protein thioredoxin (TRX1), although the exact details of this regulation were previously unclear.
- Researchers examined the binding domain of ASK1 (ASK1-TBD) and its interaction with reduced TRX1, finding that they form a stable 1:1 complex without forming disulfide bonds.
- Key residues from TRX1, specifically from its WCGPC motif, are crucial for the stability of this interaction, and structural analysis indicates that the ASK1-TBD has a compact shape, suggesting TRX1 binds effectively without significant changes to the structure of ASK1.
Article Abstract
Apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase, plays a key role in the pathogenesis of multiple diseases. Its activity is regulated by thioredoxin (TRX1) but the precise mechanism of this regulation is unclear due to the lack of structural data. Here, we performed biophysical and structural characterization of the TRX1-binding domain of ASK1 (ASK1-TBD) and its complex with reduced TRX1. ASK1-TBD is a monomeric and rigid domain that forms a stable complex with reduced TRX1 with 1:1 molar stoichiometry. The binding interaction does not involve the formation of intermolecular disulfide bonds. Residues from the catalytic WCGPC motif of TRX1 are essential for complex stability with Trp(31) being directly involved in the binding interaction as suggested by time-resolved fluorescence. Small-angle x-ray scattering data reveal a compact and slightly asymmetric shape of ASK1-TBD and suggest reduced TRX1 interacts with this domain through the large binding interface without inducing any dramatic conformational change.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148872 | PMC |
| http://dx.doi.org/10.1074/jbc.M114.583807 | DOI Listing |
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