Conserved disordered regions and ubiquitin-binding motifs within HUWE1 contribute to substrate targeting plasticity.

HUWE1 substrate targeting depends on both its largest intrinsically disordered region and conserved ubiquitin-binding motifs, enabling plasticity across diverse substrates.

• Why it matters: HUWE1 is a pleiotropic HECT-type E3 ligase, but how it selects many structurally different substrates remains unclear.
• What they did: The authors built a combinatorial cell system using global proteomics, proximity labeling, and reporter assays to map HUWE1 sequence features, defining an activity signature of substrates that accumulate when HUWE1 is impaired across multiple cell lines.
• The result: Re-expressing HUWE1 deletion mutants showed that disordered regions and ubiquitin-binding motifs contribute to targeting, and modeling/domain analysis suggests multivalent interactions engage both disordered and structured substrate regions.

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