News

Structural insights reveal how SPOP protein contributes to cancer

Erin Podolak
By Erin Podolak
Feb. 2, 2023

SPOP is the most mutated protein in prostate cancer and plays a role in endometrial, uterine and other cancers. Despite this importance, how SPOP mutations drive cancer has been incompletely understood. Scientists at St. Jude Children’s Research Hospital used cryo-electron microscopy to capture the first 3D structure of the entire SPOP assembly. The study, published in the journal Molecular Cell, revealed previously unknown SPOP interfaces that harbor clusters of cancer-causing mutations. 

The normal function of SPOP is to control the level of certain proteins within a cell. When SPOP is dysregulated through mutations, it can cause dramatic effects in the cell because protein levels are altered, triggering abnormal behaviors. SPOP may not be the fire that sets cancer ablaze, but if mismanaged, it can light the fuse. 

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

From left, Brian O’Flynn, Matthew Cuneo and Tanja Mittag
St. Jude Children's Research Hospital
From left, Brian O’Flynn, Matthew Cuneo and Tanja Mittag

Big picture understanding

Determining the 3D structure of SPOP using cryo-EM allowed the researchers to gain insights into the underlying mechanisms that drive the function of this protein both in its normal state and when mutated in cancer. By looking at how the SPOP oligomer assembles, the researchers were able to identify key interactions between regions of the protein, which had not been seen before. These were exactly the regions that are mutated in endometrial cancer. 

“Once we had the 3D structure of SPOP, we could see that the pieces of the puzzle that had been missing were inherently important for understanding how SPOP functions in cancer,” said co-first author Matthew Cuneo. “We were now able to see that what we initially thought to be regions of SPOP without functional importance are actually key to SPOP assembly and biology.”

One mutation, dramatic effects 

Previous studies had demonstrated that the SPOP protein assembles into long filaments. However, scientists could tell that the full picture had yet to be uncovered, as certain mutations unexpectedly affected this filament. 

For example, mutations in the MATH domain (the part of SPOP that binds substrates) affected the propensity of the protein to assemble and hang around in cells. The researchers also observed how a single mutation could dramatically affect how the protein forms filaments. Mutating the interface that locks the MATH domain in place completely changed the assembly of the proteins from a single to a double filament with intertwined MATH domains.

Discovering these additional protein interfaces in the filament using cryo-EM helped further explain how SPOP mutations contribute to cancer.

“Taking a broader view to look at the full-length protein gave us a deeper understanding of how mutations affect SPOP,” said co-first author Brian O’Flynn.  “The scale of the change just from one point mutation is huge. It was unexpected to see that.” 

New questions

Researchers in the field have already experimented with drugs that target the MATH domain of SPOP. Drugs could now be developed to target specifically the mutant forms of SPOP in endometrial cancer. One of the implications of this work is that one day it might be possible to differentially target SPOP based upon its functional form within the cell. 

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

This article was first published by St. Jude Children's Research Hospital. Read the original.

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Erin Podolak
Erin Podolak

Erin Podolak writes and edits stories about scientific research for St. Jude Children’s Research Hospital. She has worked as a science writer for over a decade and is a member of the National Association of Science Writers.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Bacterial protein reverses infertility by lowering cholesterol
Journal News

Bacterial protein reverses infertility by lowering cholesterol

March 24, 2023

Researchers reverse infertility in preclinical models by reducing HDL cholesterol with a bacterial virulence protein.

Offensive strategies in the lab
Feature

Offensive strategies in the lab

March 24, 2023

A love of football inspired this Iowa State undergrad’s food preservation research.

Lighting the way to undergraduate research
Annual Meeting

Lighting the way to undergraduate research

March 23, 2023

A team at Albion College is working on light-activated pharmaceuticals to target cancer and minimize damage to healthy cells.

Exploring marine science at the cellular level
Annual Meeting

Exploring marine science at the cellular level

March 21, 2023

Karlie Tischendorf, a senior at Purdue University, is scheduled to present her research on stingray venom at Discover BMB.

Assessing the risk of excess folic acid intake
News

Assessing the risk of excess folic acid intake

March 18, 2023

DNA repair genes were significantly hypermethylated in mice fed a lot of it, a Baylor team reports.

From the journals: JBC
Journal News

From the journals: JBC

March 17, 2023

With sulfur, life finds a way. Specific anti-cancer antibodies. Exercise-induced signaling cross talk. Read about recent articles on these topics.