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

Matthew J Cuneo1, Ömer Güllülü1, Mohamed-Raafet Ammar1

  • 1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Molecular Cell
|July 13, 2026
PubMed

Insights

Speckle-type POZ protein (SPOP) filaments regulate cancer by switching between active and inactive states. Activating mutations disrupt this balance, leading to uncontrolled cell growth and offering new therapeutic targets.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Speckle-type POZ protein (SPOP) is a crucial substrate receptor for the Cullin-3-RING (CRL3) ubiquitin ligase.
  • Mutations in SPOP are implicated in various cancers, with both activating and inactivating mutations driving oncogenesis.
  • SPOP's unique ability to form multivalent filaments for substrate binding contrasts with typical substrate receptor mechanisms.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of SPOP filament assembly and substrate ubiquitination.
  • To understand how mutations in SPOP lead to oncogenic gain-of-function.
  • To explore the potential of targeting SPOP's regulatory axis for cancer therapies.

Main Methods:

  • Investigated SPOP assembly states using structural and biochemical analyses.
  • Examined the impact of activating and inactivating mutations on SPOP equilibrium and substrate turnover.
  • Analyzed the role of SPOP filament formation in cellular regulation.

Main Results:

  • SPOP assemblies exist in a dynamic equilibrium between active filaments and an autoinhibited circular 'double-donut' state.
  • Activating mutations shift this equilibrium towards the active filament state, causing aberrant substrate ubiquitination.
  • Combinations of mutations reveal a tunable regulatory axis, influencing SPOP activity levels.

Conclusions:

  • SPOP filament assembly is essential for its cellular regulation and underlies gain-of-function mechanisms in cancer.
  • Understanding the SPOP equilibrium provides insights into oncogenesis driven by SPOP mutations.
  • Targeting the SPOP regulatory axis presents a promising strategy for developing novel cancer therapies.
Keywords:
Cullin ring ligaseSPOPcryo-EMendometrial cancerfilamentgain of functionhigher-order oligomerprostate cancerproteostasisubiquitin ligase

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