Scientists at St. Jude Children’s Research Hospital have cracked a mystery that cancer researchers have puzzled over for years. They discovered the structure of a protein called SPOP — and it looks like two stacked donuts. This "double-donut" shape explains why certain SPOP mutations cause cancer, even though scientists never fully understood how. The findings were published in the journal Molecular Cell.
SPOP is a protein that helps control the levels of other proteins inside cells, including ones called BRD2, BRD3, and BRD4 that can drive cancer when they become too active or too abundant. Some mutations in SPOP obviously disrupt how it binds to these cancer-related proteins, but other mutations were found in cancer patients without any clear explanation. "SPOP is unique among ubiquitin ligases in that it assembles into long filaments — no other substrate receptor we know of does this — but we didn't understand what this brings to the table," said Tanja Mittag, Ph.D., the study's lead researcher in the Department of Structural Biology at St. Jude. "Now we know that SPOP must assemble into these long filaments to be able to circularize and form the double donuts."
The team found that when SPOP is inactive, individual protein molecules link together into a large ring — the double donut — made of 22 to 30 SPOP molecules stacked in two layers. This ring is so spacious it can wrap around an entire ribosome, the tiny cellular machine that builds proteins. When SPOP gets activated by binding to a partner called Cullin-3, the structure shifts into a long, thread-like filament instead. Cancer mutations tip this balance abnormally: some push the protein toward the inactive double-donut state, while others lock it into the active filament state, bypassing the cell's normal controls.
"One of the most important roles of the double donut is that it represents an 'off' state; they are essentially an autoinhibited, inactive form of SPOP," said co-first author Matt Cuneo, Ph.D. "The cancer mutations can bypass this regulation, meaning they are no longer responding to normal cellular signals that switch SPOP between the inactive double-donut structure and the active filament."
The researchers also discovered that SPOP naturally lives in tiny compartments inside the cell nucleus called nuclear speckles. The inactive double-donut form stays inside these speckles, while overactive mutations send SPOP into the surrounding area. This gives scientists clues about where the protein goes to work.
For patients, the most hopeful part may be what comes next. "The newly identified inactive double-donut structure provides a new framework for thinking about how SPOP could be targeted in cancer," said co-first author Mohamed-Raafet Ammar, Ph.D. In other words, now that scientists understand how SPOP works like an on-off switch, they may be able to design drugs that restore the proper balance — and potentially stop certain cancers from growing.