Structural basis for cysteine-linked redox-state plasticity in mammalian methionine sulfoxide reductase A.
5 affiliations
- 1Department of Biotechnology, College of Life Sciences & Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
- 2Intercollege, Hanyang University, Seoul, 04763, Republic of Korea; School of Environment and Science, Griffith University, Brisbane, QLD, 4111, Australia.
- 3School of Environment and Science, Griffith University, Brisbane, QLD, 4111, Australia.
- 4School of Environment and Science, Griffith University, Brisbane, QLD, 4111, Australia; Institute for Biomedicine and Glycomics, Griffith University, Brisbane, QLD, 4111, Australia. Electronic address: [email protected].
- 5Department of Biotechnology, College of Life Sciences & Biotechnology, Korea University, Seoul, 02841, Republic of Korea. Electronic address: [email protected].
Abstract
Methionine sulfoxide reductase A (MsrA) protects proteins from oxidative damage through cysteine-based redox cycling, but how mammalian MsrA is structurally regulated during oxidation and reductive recycling has remained unclear. We report three crystal structures of mouse MsrA (mMsrA) that capture distinct redox states - reduced (3.0 Å), BME-trapped intermediate-like (BTIL; 1.6 Å), and oxidized (1.9 Å) - and reveal an unrecognized layer of regulation centered on Cys107. The BTIL structure visualizes catalytic Cys72 as a mixed disulfide with β-mercaptoethanol (BME) alongside a sulfenic acid at Cys107, a configuration not previously observed. The oxidized structure resolves the canonical Cys72-Cys218 disulfide together with an unexpected Cys107-Cys227 pairing that locks a C-terminal loop into a cap over the active site. LC-MS/MS mapping, MD simulations, activity assays, and thioredoxin (Trx)-trapping experiments converge on a model in which Cys72 drives catalysis, while Cys107-mediated disulfide rearrangement and Cys227-directed Trx entry gate substrate access and enzymatic regeneration - defining a noncanonical oxidized state that expands the mechanistic repertoire of mammalian MsrA under oxidative stress.
Related
- Structural Insights into a Fusion Protein between a Glutaredoxin-like and a Ferredoxin-Disulfide Reductase Domain from an Extremophile Bacterium
- Structural Plasticity and Ligand Promiscuity of CYP3A4 Revealed by Cryo-EM
- STRUCTURAL PLASTICITY ALLOWS DOUBLECORTIN AND DRUG-STABILIZED MICROTUBULES TO ACCOMMODATE EACH OTHER
- The Lysine Methyltransferase SETDB1 Alleviates Methionine- and Choline-Deficient Diet-Induced Steatohepatitis by Suppressing Ferroptosis
- Short-term methionine starvation reshapes diurnal hepatic m6A RNA methylation
BibTeX
@article{shin2026structural,
title = {{Structural basis for cysteine-linked redox-state plasticity in mammalian methionine sulfoxide reductase A.}},
author = {Byeongmin Shin and Hye-Jin Kim Hawkes and Seonha Park and Hosam Ki and Sulhee Kim and Fenil Shah and Giovanna Di Trapani and Kathryn F Tonissen and Kwang Yeon Hwang},
journal = {Redox biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104436},
url = {https://europepmc.org/article/MED/42860110},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Structural basis for cysteine-linked redox-state plasticity in mammalian methionine sulfoxide reductase A.
AU - Byeongmin Shin
AU - Hye-Jin Kim Hawkes
AU - Seonha Park
AU - Hosam Ki
AU - Sulhee Kim
AU - Fenil Shah
AU - Giovanna Di Trapani
AU - Kathryn F Tonissen
AU - Kwang Yeon Hwang
PY - 2026
DA - 2026/10/10
JO - Redox biology
DO - 10.1016/j.redox.2026.104436
UR - https://europepmc.org/article/MED/42860110
AB - Methionine sulfoxide reductase A (MsrA) protects proteins from oxidative damage through cysteine-based redox cycling, but how mammalian MsrA is structurally regulated during oxidation and reductive recycling has remained unclear. We report three crystal structures of mouse MsrA (mMsrA) that capture distinct redox states - reduced (3.0 Å), BME-trapped intermediate-like (BTIL; 1.6 Å), and oxidized (1.9 Å) - and reveal an unrecognized layer of regulation centered on Cys107. The BTIL structure visualizes catalytic Cys72 as a mixed disulfide with β-mercaptoethanol (BME) alongside a sulfenic acid at Cys107, a configuration not previously observed. The oxidized structure resolves the canonical Cys72-Cys218 disulfide together with an unexpected Cys107-Cys227 pairing that locks a C-terminal loop into a cap over the active site. LC-MS/MS mapping, MD simulations, activity assays, and thioredoxin (Trx)-trapping experiments converge on a model in which Cys72 drives catalysis, while Cys107-mediated disulfide rearrangement and Cys227-directed Trx entry gate substrate access and enzymatic regeneration - defining a noncanonical oxidized state that expands the mechanistic repertoire of mammalian MsrA under oxidative stress.
SN - 2213-2317
ER -