The acetohydroxyacid synthase (AHAS) holoenzyme catalyzes the first step of branch-chain amino acid biosynthesis and is essential for plants and bacteria. It consists of a regulatory subunit (RSU) and a catalytic subunit (CSU). The allosteric mechanism of the AHAS holoenzyme has remained elusive for decades. Here, we determined the crystal structure of the AHAS holoenzyme, revealing the association between the RSU and CSU in an A2B2 mode. Structural analysis in combination with mutational studies demonstrated that the RSU dimer forms extensive interactions with the CSU dimer, in which a conserved salt bridge between R32 and D120 may act as a trigger to open the activation loop of the CSU, resulting in the activation of the CSU by the RSU. Our study reveals the activation mechanism of the AHAS holoenzyme.

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