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Abstract In meiosis, crossovers between homologous chromosomes generate genetic diversity and are required for accurate chromosome segregation, ensuring fertility. In mammals, HEI10 is one of three pro-crossover RING-domain factors implicated in protein modification by ubiquitin and/or SUMO and characterised by their dynamic accumulation at future crossover sites. However, the molecular architecture and enzymatic activity of mammalian HEI10 have remained unknown. Here, we show that human HEI10 has E3-ubiquitin ligase activity that depends on its higher-order assembly. We report the crystal structure of the HEI10 core, revealing how a 29-nm rod-like tetramer is formed through head-to-head association of two coiled-coil dimers that results in clustering of four RING domains around the molecular centre. HEI10 tetramers self-assemble through RING, coiled-coil, and C-terminal interfaces into fibrous and spherical higher-order structures. Structure-guided mutants show that higher-order assembly is required for HEI10 to catalyse K63-linked ubiquitin chain formation in vitro , with the most active species likely corresponding to a loose, non-fibrous network of assembled HEI10 molecules. Arabidopsis thaliana HEI10 retains the tetrameric core and higher-order assembly behaviour, suggesting a conserved principle of HEI10 function.
Milburn et al. (Sun,) studied this question.