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The equilibrium between two quaternary assembly states determines the activity of SPOP and its cancer mutants

Matthew J Cuneo1, Ömer Güllülü1, Mohamed-Raafet Ammar1

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

Biorxiv : the Preprint Server for Biology
|July 16, 2025
PubMed

Insights

The ubiquitin ligase SPOP forms filaments and rings that regulate its activity. Cancer mutations alter this structure, affecting oncogenesis and suggesting new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cancer Research

Background:

  • Proteostasis is crucial for preventing oncogenesis.
  • Mutations in SPOP (Speckle-type POZ protein) are linked to various cancers.
  • The regulatory mechanisms of SPOP, a ubiquitin ligase subunit, remain unclear.

Purpose of the Study:

  • To elucidate the structural organization and regulation of SPOP.
  • To understand how SPOP mutations contribute to oncogenesis.
  • To identify potential therapeutic strategies targeting SPOP.

Main Methods:

  • Filament assembly analysis
  • Structural studies of SPOP complexes
  • Mutation analysis
  • Substrate turnover assays
  • Subcellular localization studies

Main Results:

  • SPOP filaments circularize into rings, which dimerize into large, auto-inhibited double donut structures.
  • The equilibrium between linear filaments and double donuts dictates SPOP activity.
  • Cancer-associated mutations shift this equilibrium, impacting substrate binding and localization.
  • A regulatory mechanism involving filament length and circularization explains substrate binding.

Conclusions:

  • SPOP activity is regulated by its assembly into dynamic filament and double donut structures.
  • Altered SPOP structures due to mutations influence cancer development.
  • Targeting the SPOP equilibrium presents a potential avenue for cancer therapy.

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