Abstract
ProMyelocyticLeukemia nuclear bodies (PML NBs) are stress-regulated domains directly implicated in acute promyelocytic leukemia eradication. Most TRIM family members bind ubiquitin E2s and many acquire ligase activity upon RING dimerization. In contrast, PML binds UBC9, the SUMO E2 enzyme. Here, using X-ray crystallography and SAXS characterization, we demonstrate that PML RING tetramerizes through highly conserved PML-specific sequences, which are required for NB assembly and PML sumoylation. Conserved residues implicated in RING dimerization of other TRIMs also contribute to PML tetramer stability. Wild-type PML rescues the ability of some RING mutants to form NBs as well as their sumoylation. Impaired RING tetramerization abolishes PML/RARA-driven leukemogenesis in vivo and arsenic-induced differentiation ex vivo. Our studies thus identify RING tetramerization as a key step in the NB macro-molecular scaffolding. They suggest that higher order RING interactions allow efficient UBC9 recruitment and thus change the biochemical nature of TRIM-facilitated post-translational modifications.
Highlights
ProMyelocyticLeukemia nuclear bodies (PML NBs) are stress-regulated domains directly implicated in acute promyelocytic leukemia eradication
We discovered that PML RING assembles into tetrameric torus whose formation requires highly evolutionarily conserved PML-specific residues located on the two contact points (Fig. 1b)
PML sumoylation does not contribute to NBbiogenesis[2]
Summary
ProMyelocyticLeukemia nuclear bodies (PML NBs) are stress-regulated domains directly implicated in acute promyelocytic leukemia eradication. Using X-ray crystallography and SAXS characterization, we demonstrate that PML RING tetramerizes through highly conserved PML-specific sequences, which are required for NB assembly and PML sumoylation. Our studies identify RING tetramerization as a key step in the NB macro-molecular scaffolding They suggest that higher order RING interactions allow efficient UBC9 recruitment and change the biochemical nature of TRIM-facilitated post-translational modifications. PML NBs recruit enzymes implicated in several post-translational modifications, primarily UBC9, the key E2 SUMO-conjugating enzyme, possibly facilitating partner sumoylation[2,3]. We report the crystallographic high-resolution structure of PML RING, and demonstrate that it assembles into a tetrameric torus Interfaces of these tetramers involve PML-specific sequences that are highly conserved during evolution. Our data suggest that this novel macro-molecular RING assembly may control interactions with E2s and TRIM functions
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