The mechanism of cysteine sensing by LRRC58

Abstract

Cysteine is essential for life but toxic in excess. Cells and tissues are exposed to elevated cysteine from endogenous sources and the environment yet maintain low intracellular concentrations to sustain life. Here we identify a mechanism for sensing cysteine to control its abundance and prevent toxicity and premature death. Using cryo-electron microscopy we determine structures of the CRL5L^RRC58 E3 ligase alone and in complex with the cysteine-catabolizing enzyme CDO1. We show that CDO1 interacts with LRRC58 in the vicinity of a zinc-coordinating cysteine motif, within which Cys296 becomes covalently modified upon cysteine exposure. Covalent modification of Cys296 and zinc ejection from this motif drive large structural rearrangements of LRRC58 relayed through Cys319, which destabilize CDO1 binding and position LRRC58 Lys111 for autoubiquitylation. This reorientation of LRRC58 permits CDO1 accumulation, thereby lowering intracellular cysteine. Mutation of Cys319 abrogates inhibitory rearrangement of LRRC58 upon cysteine modification. This renders the ligase constitutively active and prevents CDO1 stabilization, thereby driving systemic cysteine accumulation and premature death in animals. These findings establish the molecular basis of homeostatic cysteine sensing by LRRC58 and demonstrate its essential role in maintaining cysteine concentrations compatible with healthy life.

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BibTeX RIS

BibTeX

@misc{fink2026mechanism,
  title = {{The mechanism of cysteine sensing by LRRC58}},
  author = {E. C. Fink and H. B. Woldemichael and N. Kambdur and M. A. Sharif and T. S. Levitz and B. Srinivasu and M. Blickling and B. Zhang and J. Zhang and Y. Wang and F. Cabreiro and T. E. Wales and E. S. Fischer and E. T. Chouchani},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.03.763985},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763985v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - The mechanism of cysteine sensing by LRRC58
AU  - E. C. Fink
AU  - H. B. Woldemichael
AU  - N. Kambdur
AU  - M. A. Sharif
AU  - T. S. Levitz
AU  - B. Srinivasu
AU  - M. Blickling
AU  - B. Zhang
AU  - J. Zhang
AU  - Y. Wang
AU  - F. Cabreiro
AU  - T. E. Wales
AU  - E. S. Fischer
AU  - E. T. Chouchani
PY  - 2026
DA  - 2026/11/03
PB  - bioRxiv
DO  - 10.64898/2026.11.03.763985
UR  - https://www.biorxiv.org/content/10.64898/2026.11.03.763985v1
AB  - Cysteine is essential for life but toxic in excess. Cells and tissues are exposed to elevated cysteine from endogenous sources and the environment yet maintain low intracellular concentrations to sustain life. Here we identify a mechanism for sensing cysteine to control its abundance and prevent toxicity and premature death. Using cryo-electron microscopy we determine structures of the CRL5L^RRC58 E3 ligase alone and in complex with the cysteine-catabolizing enzyme CDO1. We show that CDO1 interacts with LRRC58 in the vicinity of a zinc-coordinating cysteine motif, within which Cys296 becomes covalently modified upon cysteine exposure. Covalent modification of Cys296 and zinc ejection from this motif drive large structural rearrangements of LRRC58 relayed through Cys319, which destabilize CDO1 binding and position LRRC58 Lys111 for autoubiquitylation. This reorientation of LRRC58 permits CDO1 accumulation, thereby lowering intracellular cysteine. Mutation of Cys319 abrogates inhibitory rearrangement of LRRC58 upon cysteine modification. This renders the ligase constitutively active and prevents CDO1 stabilization, thereby driving systemic cysteine accumulation and premature death in animals. These findings establish the molecular basis of homeostatic cysteine sensing by LRRC58 and demonstrate its essential role in maintaining cysteine concentrations compatible with healthy life.
ER  -

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