9OUW

SPOP double donut locally refined MATH domains

This is a non-PDB format compatible entry.

Summary for 9OUW

• Entry DOI: 10.2210/pdb9ouw/pdb
• EMDB information: 70883
• Descriptor: Speckle-type POZ protein (1 entity in total)
• Functional Keywords: ubiquitination, protein degradation, protein oligomer, substrate adapter, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 336770.22

Authors

Cuneo, M.J. (deposition date: 2025-05-29, release date: 2025-07-30)

Primary citation

Cuneo, M.J.,Gullulu, O.,Ammar, M.R.,Gui, X.,Churion, K.,Turk, M.,O'Flynn, B.G.,Sabri, N.,Mittag, T.
The equilibrium between two quaternary assembly states determines the activity of SPOP and its cancer mutants.
Biorxiv, 2025

PubMed Abstract: Proteostasis is critical for preventing oncogenesis. Both activating and inactivating mutations in the ubiquitin ligase subunit SPOP result in oncogenesis in different tissues. SPOP assembles into filaments that are multivalent for substrates, and substrates have multiple weak motifs for SPOP that are not activated via post-translational modifications. It is thus unclear how regulation is achieved. Here, we show that SPOP filaments circularize into rings that dimerize into up to 2.5 MDa-large, auto-inhibited double donuts. The equilibrium between double donuts and linear filaments determines SPOP activity. Activating and deactivating cancer mutations shift the equilibrium towards the filament or the double donut, respectively, and this influences substrate turnover and subcellular localization. This regulatory mechanism requires long filaments that can circularize into rings, likely explaining the presence of multiple weak SPOP-binding motifs in substrates. Activating and deactivating mutations combine to give rise to intermediate activities, suggesting new levers for cancer therapies.

PubMed: 40666954
DOI: 10.1101/2025.06.19.659812

Experimental method

ELECTRON MICROSCOPY (3.2 Å)