Research on RAS-driven cancers yields key finding about developmental syndrome also caused by RAS protein

By investigating the biological structure of a protein known to cause a genetic skin condition, scientists at the Frederick National Laboratory for Cancer Research validated a decades-old hypothesis about disease implications surrounding the protein’s mutation in a recent study published in Cell Reports

The RAS Structural Biology team is part of the National Cancer Institute’s RAS Initiative, housed at Frederick National Laboratory. The initiative studies proteins encoded by RAS gene mutations, which drive more than 20 percent of human cancers. 

In this study, the team provided a structural basis for the cause of RASopathies, developmental syndromes caused by gene mutations affecting RAS proteins. RASopothies are not cancer, yet research on RAS-related cancers has shed light on these diseases. 

A three dimensional digital graphic of the KRAS protein structure.
Surface representation of the crystal structure of KRAS (beige) in complex with SPRED1 (pink) and Neurofibromin (green). Image provided by the RAS Structural Biology Team.

Using protein crystallography, a technique used to determine the molecular structure of a protein by X-ray analysis of its crystallized form, the team solved the three-dimensional structure of the protein-protein complex formed by KRAS, SPRED1, and Neurofibromin. Inside the cell, the SPRED1 protein brings the Neurofibromin protein close to the RAS protein where Neurofibromin suppresses RAS activity. If a mutation impacts the SPRED1- Neurofibromin binding, then this regulation cannot take effect. 

While scientists have known about SPRED1 and its role in regulating RAS activity since 2010, team lead Dhirendra Simanshu, Ph.D. said the recent study showed how SPRED1 interacts with Neurofibromin and regulates RAS activity in normal and pathologic conditions. The work described in this study was carried out by Wupeng Yan, Ph.D. a post-doctoral fellow in the RAS structural biology team in collaboration with Frank McCormick’s laboratory at the University of California, San Francisco.   

“Crystal structure explains the relationship between SPRED1 protein mutations and Legius syndrome, a rare genetic skin condition and RASopathy syndrome,” Simanshu said. “Like trying to fit the wrong puzzle pieces together, if the SPRED1 protein is mutated, it can no longer effectively interact with Neurofibromin thus is unable to regulate RAS activity.”   

While there’s still much unknown, Simanshu said this study has substantial biological and clinical ramifications. The structural information can help provide the grounds for scientists to explore targeted therapies directed against RASopathy syndrome.