Structural and biochemical insight into allosteric regulation of the human 2-aminoadipic semialdehyde synthase.

Cryo-EM reveals the full-length 400-kilodalton tetrameric human AASS complex with substrates and products bound to both catalytic domains, enabling mapping of allosteric regulation.

• Why it matters: Lysine degradation disorders are clinically important, but how AASS is regulated remains unclear, limiting mechanistic understanding and potential therapeutic targeting.
• What they did: The authors solved a cryo-EM structure of AASS with LOR and SDH catalytic domains bound to substrates/products, then identified allosteric compounds acting via cysteine-414 and shifting the pH optimum. They also performed mutagenesis of the allosteric Cys 414 and assessed conformational and activity changes.
• The result: Altering Cys 414 strongly affects AASS conformation and activity despite being >12 angstrom from the active site, suggesting hinge-proximal changes can reshape catalysis and that allosteric cysteines may be broadly useful targets.

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