A conserved urate oxidase helix-tiling assembly promotes metabolic robustness in peroxisomes.

Abstract

Cells organize metabolism within a crowded intracellular milieu, yet the structural logic and functional consequences of supramolecular enzyme assemblies in vivo remain poorly defined. Here, using in situ cryo-electron tomography, we identify a previously uncharacterized high-order architecture of urate oxidase in mouse liver. Urate oxidase homotetramers assemble into helical fibers that tile laterally to form a stable, porous lamellar scaffold. This organization preserves extensive accessible surface area while permitting efficient substrate and product exchange. Structure-guided perturbation abolishes the assembly in vivo without measurably altering intrinsic catalytic activity, indicating a primary role in spatial organization rather than allosteric regulation. Consistent with this, the assembled state enhances resistance to thermal, proteolytic and oxidative stress, supporting sustained activity in the peroxide-rich peroxisomal matrix. Conserved across mammals, this architecture reveals a strategy for metabolic compartmentalization that couples efficient catalysis to increased molecular robustness without the trade-off between supramolecular assembly and enzyme accessibility.

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