A cotranslational role for selenocysteine in productive protein folding

Replacing selenocysteine with cysteine in the ER selenoprotein SELENOM redirects biosynthesis to a stable domain-swapped homodimer assembly pathway.

• Why it matters: Sec is usually viewed only as a catalytic determinant in mature selenoproteins, leaving its potential contributions during protein biogenesis unclear.
• What they did: The authors used SELENOM as a model and combined biochemical and structural analyses, including extensive active-site mutagenesis, to test whether altered active-site chemistry explains the dimer phenotype.
• The result: Reintroducing Sec at alternative positions suppresses domain-swapped dimer formation, even when Sec is placed in a cleaved signal peptide and is absent from the mature protein, implying Sec incorporation timing reshapes folding outcomes.

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