How the SPOP Protein Plays a Role in Cancer

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Multiple studies have found that speckle-type POZ protein (SPOP) can suppress tumorigenesis in several types of human malignancies, including prostate, lung, stomach, liver, colon and endometrial cancer. SPOP is the most commonly mutated protein in prostate cancer. However, it is not fully understood how SPOP mutations cause cancer. Now scientists at St. Jude Children’s Research Hospital report using cryo-electron microscopy (cryo-EM) to capture the first 3D structure of the entire SPOP assembly.

Their findings are published in molecular cell in an article titled, “Higher Order SPOP Assembly Reveals a Basis for Dysregulation of Cancer Mutants.”

“The speckle-type POZ protein (SPOP) functions in the Cullin3-RING ubiquitin ligase (CRL3) as a receptor for the recognition of substrates involved in cell growth, survival and signaling,” the researchers wrote. “SPOP mutations have been attributed to the development of many cancers, including prostate and endometrial cancer.”

From left to right: Brian O’Flynn, PhD, Matthew Cuneo, PhD, and Tanja Mittag, PhD [St. Jude Children’s Research Hospital]

“The prostate cancer-associated mutations are well understood,” explains corresponding author Tanja Mittag, PhD, St. Jude Department of Structural Biology. “They reside at the substrate binding site and prevent SPOP from recognizing its substrates. But mutations found in patients with endometrial cancer and other cancers have been puzzling. The mutated sites did not appear to be important for SPOP function, at least when looking at previous structures.”

Determining the 3D structure of SPOP using cryo-EM allowed the researchers to understand the underlying mechanisms that drive the function of this protein, both in its normal state and when it is mutated in cancer.

“Once we had the 3D structure of SPOP, we could see that the pieces of the puzzle that were missing were inherently important to understanding how SPOP functions in cancer,” said co-first author Matthew Cuneo, PhD, St. Jude Department of structural biology. “We could now see that what we initially thought were SPOP regions of no functional importance are actually key to SPOP assembly and biology.”

Previous studies have shown that the SPOP protein assembles into long filaments. Discovering the additional protein interfaces in the filament using cryo-EM helped further explain how SPOP mutations contribute to cancer.

“Having a broader view of the full-length protein gave us a better understanding of how mutations affect SPOP,” says co-first author Brian O’Flynn, PhD, St. Jude Department of Structural Biology. “The scale of change from just one point mutation is enormous. That was unexpected to see.”

“In addition to the questions this research answers, what’s exciting is that for scientists asking about SPOP, the possibilities have really opened up,” O’Flynn added.

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