Large-scale quaternary structural transitions underlie gain of function of SPOP cancer mutations.

SPOP mutations cause cancer by shifting a structural equilibrium from autoinhibited to active filament states, leading to abnormal substrate turnover.

• Why it matters: Understanding how SPOP mutations alter its function is crucial because both activating and inactivating mutations contribute to cancer development, yet their mechanisms remain unclear.
• What they did: Researchers analyzed the structural states of SPOP, revealing an equilibrium between an active filament form and an autoinhibited "double-donut" state, and how mutations shift this balance.
• The result: Findings show that filament assembly is essential for SPOP regulation and that mutations can tune its activity, providing insights for targeted cancer therapies.