O2-Coupled Copper–Cysteine Redox Chemistry Drives Oxidative Modifications and Higher-Order Assembly of Monomeric Transthyretin
- 1Korea Advanced Institute of Science and Technology (KAIST) , , ,
- 2Daegu Gyeongbuk Institute of Science and Technology (DGIST) , , ,
Abstract
Copper–cysteine (Cu–Cys) coordination is pervasive in biology, yet how Cu–thiol redox chemistry engages O2 and translates into protein-level consequences remains incompletely understood. Here, we establish a generalizable protein-based platform that directly captures O2-coupled Cu(II)–Cys redox processes and delineates their structural and functional outcomes. Integrated spectroscopic, mass spectrometric, and computational investigations reveal that Cu(II) coordination to a protein Cys residue initiates redox cycling that generates thiyl radicals and/or disulfide radical anions. This chemically defined process drives disulfide bond formation together with O2-dependent oxidative transformations, producing site-specific Cys modifications, dityrosine cross-links, and higher-order protein assemblies. Under these conditions, these structural changes abolish the protein’s anti-amyloidogenic activity and result in apoptotic responses. By directly linking Cu–thiol redox chemistry to protein oxidation and aggregation, this work establishes a fundamental chemical principle by which redox-active metal ions govern protein fate under aerobic conditions. More broadly, these findings provide a mechanistic framework for understanding how metal-mediated oxidative chemistry contributes to protein misfolding and aggregation in human diseases.
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BibTeX
@article{yi2026o2coupled,
title = {{O2-Coupled Copper–Cysteine Redox Chemistry Drives Oxidative Modifications and Higher-Order Assembly of Monomeric Transthyretin}},
author = {Yelim Yi and Wooyeol Ryu and Bokyung Kim and Srinivasan Muniyappan and Jin Hae Kim and Kiyoung Park and Mi Hee Lim},
journal = {ACS Central Science},
year = {2026},
month = oct,
doi = {10.1021/acscentsci.6c00619},
url = {https://pubs.acs.org/acscii/article/12/10/1659/5444810/O2-Coupled-Copper-Cysteine-Redox-Chemistry-Drives},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - O2-Coupled Copper–Cysteine Redox Chemistry Drives Oxidative Modifications and Higher-Order Assembly of Monomeric Transthyretin
AU - Yelim Yi
AU - Wooyeol Ryu
AU - Bokyung Kim
AU - Srinivasan Muniyappan
AU - Jin Hae Kim
AU - Kiyoung Park
AU - Mi Hee Lim
PY - 2026
DA - 2026/10/05
JO - ACS Central Science
DO - 10.1021/acscentsci.6c00619
UR - https://pubs.acs.org/acscii/article/12/10/1659/5444810/O2-Coupled-Copper-Cysteine-Redox-Chemistry-Drives
AB - Copper–cysteine (Cu–Cys) coordination is pervasive in biology, yet how Cu–thiol redox chemistry engages O2 and translates into protein-level consequences remains incompletely understood. Here, we establish a generalizable protein-based platform that directly captures O2-coupled Cu(II)–Cys redox processes and delineates their structural and functional outcomes. Integrated spectroscopic, mass spectrometric, and computational investigations reveal that Cu(II) coordination to a protein Cys residue initiates redox cycling that generates thiyl radicals and/or disulfide radical anions. This chemically defined process drives disulfide bond formation together with O2-dependent oxidative transformations, producing site-specific Cys modifications, dityrosine cross-links, and higher-order protein assemblies. Under these conditions, these structural changes abolish the protein’s anti-amyloidogenic activity and result in apoptotic responses. By directly linking Cu–thiol redox chemistry to protein oxidation and aggregation, this work establishes a fundamental chemical principle by which redox-active metal ions govern protein fate under aerobic conditions. More broadly, these findings provide a mechanistic framework for understanding how metal-mediated oxidative chemistry contributes to protein misfolding and aggregation in human diseases.
SN - 2374-7943
SN - 2374-7951
ER -