The mechanism of cysteine sensing by LRRC58

Cryo-EM structures show that cysteine exposure covalently modifies LRRC58 at Cys296, triggers zinc ejection, and drives rearrangements that destabilize CDO1 binding.

• Why it matters: Cells must keep intracellular cysteine low despite elevated extracellular or endogenous supply to avoid toxicity and premature death.
• What they did: The CRL5L^RRC58 E3 ligase was visualized alone and with CDO1 by cryo-electron microscopy, and cysteine-dependent covalent modification at Cys296 was mapped to downstream structural changes.
• The result: Cys296 modification and zinc loss reorient LRRC58 to enable Lys111 autoubiquitylation, destabilizing CDO1 binding and allowing CDO1 accumulation to lower intracellular cysteine; Cys319 mutation disrupts this control and causes systemic cysteine accumulation and premature death in animals.

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